Methods for manipulating upper gastrointestinal transit, blood flow, and satiety, and for treating visceral hyperalgesia

ABSTRACT

Disclosed is a method of manipulating the rate of upper gastrointestinal transit of a substance in a mammal. Also disclosed are methods of manipulating satiety and post-prandial visceral blood flow. A method of treating visceral pain or visceral hypersensitivity in a human subject is also described. A method for prolonging the residence time of an orally or enterally administered substance by promoting its dissolution, bioavailability and/or absorption in the small intestine is also described. These methods are related to a method of transmitting to and replicating at a second location in the central nervous system a serotonergic neural signal originating at a first location in the proximal or distal gut of a mammal and/or a method of transmitting to and replicating at a second location in the upper gastrointestinal tract a serotonergic neural signal originating at a first location in the proximal or distal gut.

This application is a division of U.S. patent application Ser. No.10/810,020, filed Mar. 26, 2004, which is a division of U.S. patentapplication Ser. No. 09/837,797, filed Apr. 17, 2001, allowed, which isa continuation-in-part of U.S. patent application Ser. No. 09/374,142,filed on Aug. 11, 1999, and issued as U.S. Pat. No. 6,861,053 on Mar. 1,2005, and also a continuation-in-part of U.S. patent application Ser.No. 09/374,143, filed on Aug. 11, 1999, and issued as U.S. Pat. No.6,562,629 on May 11, 2003, and also a continuation-in-part of U.S.application Ser. No. 09/546,119, filed on Apr. 10, 2000 and issued asU.S. Pat. No. 6,558,708 on May 6, 2003, which is a continuation-in-partof U.S. patent application Ser. No. 09/420,046, filed Oct. 18, 1999,abandoned, which is a continuation-in-part of U.S. patent applicationSer. No. 09/359,583, filed on Jul. 22, 1999, abandoned, which was acontinuation of U.S. patent application Ser. No. 08/832,307, filed onApr. 3, 1997, and issued as U.S. Pat. No. 5,977,175 on Nov. 2, 1999,which was a continuation of U.S. patent application Ser. No. 08/442,843,filed on May 17, 1995, abandoned, and claims priority to PCTapplications; PCT/01/11238 filed on Apr. 7, 2001; PCT/US00/22168 filedAug. 11, 2000; and PCT/US00/22030 filed Aug. 11, 2000.

FIELD OF THE INVENTION

The present invention relates to methods and pharmaceutical compositionsfor controlling the presentation of and response to lumenal content inthe gastrointestinal tract.

BACKGROUND OF THE INVENTION

A principal function of the gastrointestinal tract is to process andabsorb food. The stomach, which is both a storage and digestive organ,works to optimize the conditions for the digestion and absorption offood in the small intestine. Following the stomach and preceding thelarge bowel (colon) is the small intestine, which comprises threeregions: the duodenum, jejunum, and ileum. A major function of the smallintestine is one of absorption of digested nutrients. motilitymechanisms which are set in motion by the composition of the mealingested. Specific receptors for fats and proteins, and the osmolality,acidity and particle size of the meal activate propulsive and inhibitoryreactions, which modulate transit and thus absorption. In normal humansubjects, the mechanisms that regulate gastrointestinal transit can,under some circumstances, be sensitized or desensitized in response tothe subject's recent dietary history. (K. M. Cunningham et al.,Gastrointestinal adaptation to diets of differing fat composition inhuman volunteers, Gut 32(5):483-86 [1991]).

The rate of transit through the small intestine is of great significancefor the rate and extent of absorption from the small intestine.Disruption of the normal digestive and absorptive processes frequentlymanifests as a variety of syndromes, such as, malnutrition, weight loss,diarrhea, steatorrhea, vitamin deficiency, electrolyte imbalance, andthe like. Chronic diarrhea is a common problem found in a variety ofgastrointestinal disorders where water, solutes and nutrients aremalabsorbed (Read, N. W., Diarrhea motrice, Clin. Gastroenterol. 15:657-86 [1986]). Specifically, conditions such as short bowel syndrome,postgastrectomy dumping and ileal resection can lead to symptoms such aspostprandial distension, cramping, abdominal pain, gaseousness, nausea,palpitations, flushing, steatorrhea or weight loss. These symptoms canpersist despite the use of anti-diarrheal medications, anticholinergicagents (Ivey, K J., Are anticholinergics of use in the irritable bowelsyndrome?, Gastroenterology 68: 1300-07 [1975]), somatostatin analogues(Reasbeck P G, and A M Van Rij, The effect of somatostatin on dumpingafter surgery: A preliminary report, Surgery 1986; 99: 462-468 [1986]),conjugated bile acid replacement therapy (C. Gruy-Kapral et al.,Conjugated bile acid replacement therapy for short-bowel syndrome,Gastroenterol. 116:15-21 [1999]), or large quantities of opiates(O'Brien, J. D. et al., Effect of codeine and loperamide on upperintestinal transit and absorption in normal subjects and patients withpostvagotomy diarrhea, Gut 19: 312-18 [1988]). Additionally, even withtreatment, fecal loss of water, solutes and nutrients can still be soexcessive in some patients that long term use of parenteral fluids andnutrition can be required for survival (Rombeau, J. L. and R. H.Rolandelli, Enteral and parenteral nutrition in patients with entericfistulas and short bowel syndrome, Surg. Clin. North Am. 67:551-571[1989]).

Abnormally slow gastrointestinal transit time can also have painful andserious consequences. Opioids (e.g., morphine), used for short-term orlong-term pain management, commonly causes a slowing of gastrointestinaltransit that can lead to bowel obstruction (ileus) or constipation.(E.g., Murthy, B. V. et al., Intestinal pseudo-obstruction associatedwith oral morphine, Eur. J. Anaesthesiol. 15(3):370-71 [1998]). Chronicconstipation can result in complications including hemorrhoids, analfissure, rectal prolapse, stercoral ulcer, melanosis coli, fecalimpaction, fecal incontinence, ischemic colitis, colonic volvulus,colonic perforation, encopresis, and urinary retention. Delayed transitcan also be a manifestation of a motility disorder such as idiopathicchronic intestinal pseudo-obstruction.

The small intestine is also an important site for the absorption ofpharmacological agents. The proximal part of the small intestine has thegreatest capacity for absorption of drugs. Intestinal absorption ofdrugs is influenced to a great extent by many of the same basic factorsthat affect the digestion and absorption of nutrients, water andelectrolytes.

Absorption of a drug in the gastrointestinal tract is a function ofcharacteristics of the drug, such as its molecular structure, as well asattributes of the gastrointestinal tract. The rate of absorption ofcertain drugs, which are absorbed slowly and usually incompletely,varies according to the small intestinal transit time. Intestinaltransit is important in the design of pharmaceutical preparations,especially when the absorption site of a drug is located in a particularsegment of the gastrointestinal tract.

Many drugs and dosage formulations have been and continue to bedeveloped because of the need to overcome the physiological andphysicochemical limitations associated with drug delivery such as poorstability, short biological half-life, inefficient absorption and poorbioavailability. Applications of controlled release technology havemoved towards control of absorption via regulation of the input to thegastrointestinal tract. However, recent pharmaceutical attempts to altergastric emptying and small intestinal transit times have not been verysuccessful. (Khosla and Davis, J. Pharm. Pharmacol. 39:47-49 [1987];Davis et al., Pharm. Res. 3:208-213 [1986]).

For drug absorption to proceed efficiently, the drug must first arriveat a normal absorbing surface in a form suitable for absorption; it mustremain there long enough in a form and in a concentration that enhanceabsorption; and it must be absorbed by a normal epithelial cell withoutbeing metabolized by that cell. Accordingly, considerable advantagewould be obtained if a pharmaceutical dosage form could be retained fora longer period of time within the stomach and/or the small intestinefor proper absorption to occur.

The period of time during which nutrients and/or drugs are in contactwith the mucosa of the small intestine is crucial for the efficacy ofdigestion and absorption. Inadequate residence time can lead to fecalloss of nutrients and diarrhea. Therefore, modulation of the motilityrate and transit time of nutrients and/or drugs through thegastrointestinal tract will ensure optimal utilization of the absorptivesurface, as well as prevent transport mechanisms from being overloaded(which could occur if substrates were passed on too rapidly and exceededthe absorptive capacity of already maximally loaded surfaces in thesmall intestine).

The speed of transit through the small intestine is normally regulatedby inhibitory mechanisms located in the proximal and distal smallintestine known as the jejunal brake and the ileal brake. Inhibitoryfeedback is activated to slow transit when end products of digestionmake contact with nutrient sensors of the small intestine. (E.g., Lin,H. C., U.S. Pat. No. 5,977,175; Dobson, C. L. et al., The effect ofoleic acid on the human ileal brake and its implications for smallintestinal transit of tablet formulations, Pharm. Res. 16(1):92-96[1999]; Lin, H. C. et al., Intestinal transit is more potently inhibitedby fat in the distal (Ileal brake) than in the proximal (jejunal brake)gut, Dig. Dis. Sci. 42(1):19-25 [1997]; Lin, H. C. et al., Jejunalbrake: inhibition of intestinal transit by fat in the proximal smallintestine, Dig. Dis. Sci., 41(2):326-29 [1996a]).

Specifically, jejunal and ileal brakes slow transit by the release ofgut peptides such as peptide YY and by the activation of neural pathwayssuch as those involving endogenous opioids. (Lin, H. C. et al,Fat-induced ileal brake in the dog depends on peptide YY, Gastroenterol.110(5):1491-95 [1996b]). Transit is then slowed by the stimulation ofnonpropagative intestinal contractions which inhibit movement of thelumenal content. The removal or impairment of these inhibitorymechanisms can lead to abnormally rapid transit. For example, inpatients with a history of resection of the terminal ileum, intestinaltransit can become uncontrolled and abnormally accelerated when theileal brake is no longer intact. Time for processing of food can then beso reduced that few end products of digestion are available to triggerthe jejunal brake as the remaining inhibitory mechanism.

Peptide YY and its analogs or agonists have been used to manipulateendocrine regulation of cell proliferation, nutrient transport, andintestinal water and electrolyte secretion. (E.g., Balasubramaniam,Analogs of peptide yy and uses thereof, U.S. Pat. No. 5,604,203;WO9820885A1; EP692971A1; Croom et al, Method of enhancing nutrientuptake, U.S. Pat. No. 5,912,227; Litvak, D. A. et al, Characterizationof two novel proabsorptive peptide YY analogs, BIM-43073D andBIM-43004C, Dig. Dis. Sci. 44(3):643-48 [1999]). A role for peptide YYin the regulation of intestinal motility, secretion, and blood flow hasalso been suggested, as well as its use in a treatment of malabsorptivedisorders (Liu, C. D. et al., Peptide YY: a potential proabsorbtivehormone for the treatment of malabsorptive disorders, Am. Surg.62(3):232-36 [1996]; Liu, C. D. et al., Intraluminal peptide YY inducescolonic absorption in vivo, Dis. Colon Rectum 40(4):478-82 [1997];Bilchik, A. J. et al., Peptide YY augments postprandial small intestinalabsorption in the conscious dog, Am. J. Surg. 167(6):570-74 [1994]).

Lin et al. immuno-neutralized peptide YY in vivo to block the ilealbrake response and, thus, showed that it is mediated by peptide YY.(Lin, H. C. et al., Fat-induced ileal brake in the dog depends onpeptide YY, Gastroenterology, 110(5):1491-95 [1996b]). Serum levels ofpeptide YY increase during the ileal brake response to nutrient infusioninto the distal ileum. (Spiller, R. C. et al., Further characterisationof the ‘ileal brake’ reflex in man—effect of ileal infusion of partialdigests of fat, protein, and starch on jejunal motility and release ofneurotensin, enteroglucagon, and peptide YY, Gut, 29(8):1042-51 [1988];Pironi, L. et al., Fat-induced ileal brake in humans: a dose-dependentphenomenon correlated to the plasma levels of peptide YY.,Gastroenterology, 105(3):733-9 [1993]; Dreznik, Z. et al., Effect ofileal oleate on interdigestive intestinal motility of the dog, Dig. Dis.Sci., 39(7):1511-8 [1994]; Lin, C. D. et al., Interluminal peptide YYinduces colonic absorption in vivo, Dis. Colon Rectum, 40(4):478-82[April 1997]). In contrast, in vitro studies have shown peptide YYinfused into isolated canine ileum dose-dependently increased phasiccircular muscle activity. (Fox-Threlkeld, J. A. et al., Peptide YYstimulates circular muscle contractions of the isolated perfused canineileum by inhibiting nitric oxide release and enchancing acetylcholinerelease, Peptides, 14(6):1171-78 [1993]).

Kreutter et al. taught the use of β₃-adrenoceptor agonists andantagonists for the treatment of intestinal motility disorders, as wellas depression, prostate disease and dyslipidemia (U.S. Pat. No.5,627,200).

Bagnol et al. reported the comparative immunovisualization of mu andkappa opioid receptors in the various cell layers of the ratgastrointestinal tract, including a comparatively large number of kappaopioid receptors in the myenteric plexus (Bagnol, D. et al., Cellularlocalization and distribution of the cloned mu and kappa opioidreceptors in rat gastrointestinal tract, Neuroscience, 81(2):579-91[1997]). They suggested that opioid receptors can directly influenceneuronal activity in the gastrointestinal tract.

Kreek et al. taught the use of opioid receptor antagonists, such asnaloxone, naltrexone, and nalmefene, for the relief of gastrointestinaldysmotility. (Kreek et al., Method for controlling gastrointestinaldysmotility, U.S. Pat. No. 4,987,136). Riviere et al. taught the use ofthe opioid receptor antagonist fedotozine in the treatment of intestinalobstructions (Riviere, P. J. M. et al., U.S. Pat. No. 5,362,756).Opioid-related constipation, the most common chronic adverse effect ofopioid pain medications in patients who require long-term opioidadministration, such as patients with advanced cancer or participants inmethadone maintenance, has been treated with orally administeredmethylnaltrexone and naloxone. (Yuan, C. S. et al., Methylnaltrexone forreversal of constipation due to chronic methadone use: a randomizedcontrolled trial, JAMA 283(3):367-72 [2000]; Meissner, W. et al., Oralnaloxone reverses opioid-associated constipation, Pain 84(1):105-9[2000]; Culpepper-Morgan, J. A., et al., Treatment of opioid-inducedconstipation with oral naloxone: a pilot study, Clin. Pharmacol. Ther.52(1):90-95 [1992]; Yuan, C. S. et al., The safety and efficacy of oralmethylnaltrexone in preventing morphine-induced delay in oral-cecaltransit time, Clin. Pharmacol. Ther. 61(4):467-75 [1997]; Santos, F. A.et al., Quinine-induced inhibition of gastrointestinal transit in mice:possible involvement of endogenous opioids, Eur. J. Pharmacol.,364(2-3):193-97 [1999]. Naloxone was also reported to abolish the ilealbrake in rats (Brown, N. J. et al., The effect of an opiate receptorantagonist on the ileal brake mechanism in the rat, Pharmacology,47(4):230-36 [1993]).

Receptors for 5-Hydroxytryptamine (5-HT), also known as serotonin, havebeen localized on various cells of the gastrointestinal tract. (Gershon,M. D., Review article: roles played by 5-hydroxytryptamine in thephysiology of the bowel, Aliment. Pharmacol. Ther., 13 Suppl 2:15-30[1999]; Kirchgessner, A. L. et al., Identification of cells that express5-hydroxytryptamine1A receptors in the nervous systems of the bowel andpancreas, J. Comp. Neurol., 15:364(3):439-455 [1996]). Brown et al.reported that subcutaneous administration of 5-HT3 receptor antagonists,granisetron and ondansetron, in rats delayed intestinal transit of abaked bean meal but abolished the ileal brake induced by ileal infusionof lipid. They postulated the presence of 5-HT3 receptors on afferentnerves that initiate reflexes that both accelerate and delay intestinaltransit. (Brown, N. J. et al., Granisetron and ondansetron: effects onthe ileal brake mechanism in the rat, J. Pharm. Pharmacol. 45(6):521-24[1993]). Kuemmerle et al. reported neuro-endocrine 5-HT-mediation ofmotilin-induced accelerated gastrointestinal motility. (Kuemmerle, J. F.et al., Serotonin neural receptors mediate motilin-induced motility inisolated, vascularly perfused canine jejunum, J. Surg. Res.,45(4):357-62 [1988]).

5-HT is a mediator for the so-called “peristaltic reflex” in themammalian colon, which mediates colonic evacuation. (E.g., Grider, J. R.et al., 5-Hydroxytryptamine4 receptor agonists initiate the peristalticreflex in human, rat, and guinea pig intestine, Gastroenterology,115(2):370-80 [1998]; Jin, J. G. et al., Propulsion in guinea pig coloninduced by 5-hydroxytryptamine (HT) via 5-HT4 and 5-HT3 receptors, J.Pharmacol. Exp. Ther., 288(1):93-97 [1999]; Foxx-Orenstein, A. E. etal., 5-HT4 receptor agonists and delta-opioid receptor antagonists actsynergistically to stimulate colonic propulsion, Am J. Physiol., 275(5Pt. 1):G979-83 [1998]; Foxx-Orenstein, A. E., Distinct 5-HT receptorsmediate the peristaltic reflex induced by mucosal stimuli in human andguinea pig intestine, Gastroenterology 111(5):1281-90 [1996]; Wade, P.R. et al., Localization and function of a 5-HT transporter in cryptepithelia of the gastrointestinal tract, J. Neurosci., 16(7):2352-64[1996]).

The intestinal response to 5-HT has been best described in terms of theperistaltic reflex in in vitro models. Bulbring and Crema first showedthat luminal 5-HT resulted in peristalsis (Bulbring et al., J. Physiol.140:381-407 [1959]; Bulbring et al., Brit. J. Pharm. 13:444-457 [1958]).Since the stimulation of peristalsis by 5-HT was unaffected by extrinsicdenervation (Bulbring et al., QJ Exp. Physiol. 43:26-37 [1958]), theperistaltic reflex was considered to be intrinsic to the enteric nervoussystem. Using a modified Trendelenburg model that compartmentalized theperistaltic reflex into the sensory limb, the ascending contraction limb(orad to stimulus) and the descending relaxation limb (aborad tostimulus), Grider, et al. reported that (1) mucosal stimulation but notmuscle stretch released 5-HT to activate a primary sensory neuron torelease calcitonin gene-related peptide (CGRP) (Grider et al., Am. J.Physiol. 270:G778-G782 [1996]) via 5-HT4 receptors in humans and rats(also 5-HT1p in rats) and 5-HT3 receptors in guinea pigs; (2)cholinergic interneurons are then stimulated by CGRP to initiate bothascending contraction via an excitatory motor neuron that depends onsubstances P and K and acetylcholine (Grider et al., Am. J. Physiol.257:G709-G714 [1989]) and descending relaxation (Grider, Am. J. Physiol.266:G1139-G1145 [1994]; Grider et al. [1996], Jin et al., J. Pharmacol.Exp. Ther. 288:93-97 [1999]) via an inhibitory motor neuron that dependson pituitary adenylate cyclase-activating peptide (PACAP), nitric oxideand vasoactive inhibitory peptide (VIP)(Grider et al., Neuroscience54:521-526 [1993]; Grider et al., J. Auton. Nerv. Syst. 50:151-159[1994]); and (3) peristalsis is controlled by [a] an opioid pathway thatinhibits descending relaxation by suppressing the release of VIP; [b] asomatostatin pathway that inhibits this opioid pathway (Grider, Am. J.Physiol. 275:G973-G978 [1998]); and [c] a GABA (Grider, Am. J. Physiol.267:G696-G701 [1994]) and a gastrin releasing peptide (GRP) (Grider,Gastroenterol. 116:A1000 [1999]) pathway that stimulate VIP release. Anopioid pathway that inhibits the excitatory motor neurons responsiblefor ascending contraction has also been described (Gintzler et al., Br.J. Pharmacol. 75:199-205 [1982]; Yau et al., Am. J. Physiol. 250:G60-G63[1986]). These observations are consistent with neuroanatomic andelectrophysiological observations.

In addition, mucosal stroking has been found to induce 5-HT release byintestinal mucosal cells, which in turn activates a 5-HT4 receptor onenteric sensory neurons, evoking a neuronal reflex that stimulateschloride secretion (Kellum, J. M. et al., Stroking human jejunal mucosainduces 5-HT release and Cl⁻ secretion via afferent neurons and 5-HT4receptors, Am. J. Physiol. 277(3 Pt 1):G515-20 [1999]).

Agonists of 5-HT4/5, 5-HT3 receptors, as well as opioid Δ receptorantagonists, were reported to facilitate peristaltic propulsive activityin the colon in response to mechanical stroking, which causes theendogenous release of 5-HT and calcitonin gene-related protein (CGRP) inthe stroked mucosal area. (Steadman, C. J. et al., Selective5-hydroxytrypamine type 3 receptor antagonism with ondansetron astreatment for diarrhea-predominant irritable bowel syndrome: a pilotstudy, Mayo Clin. Proc. 67(8):732-38 [1992]). Colonic distension alsoresults in CGRP secretion, which is associated with triggering theperistaltic reflex.

On the other hand, gastric distension is thought to be one of manyfactors inducing satiety and/or suppressing the rate of ingestion.(Bergstrom, J., Mechanism of uremic suppression of appetite, J. Ren.Nutr. 9(3):129-32 [1999]; Phillips, R. J. and Powley, T. L., Gastricvolume rather than nutrient content inhibits food intake, Am. J.Physiol. 271(3 Pt 2); R766-69 [1996]; Pappas, T. N. et al., Gastricdistension is a physiologic satiety signal in the dog, Dig. Dis. Sci.34(10:1489-93 [1989]; Lepionka, L. et al., Proximal gastric distensionmodifies ingestion rate in pigs, Reprod. Nutr. Dev. 37(4):449-57 [1997];McHugh, P R. and Moran, T. H., The stomach, cholecystokinin, andsatiety, Fed. Proc. 45(5):1384-90 [1986]; Lin, H. C. et al., Frequencyof gastric pacesetter potential depends on volume and site ofdistension, Am. J. Physiol. 270(3 Pt 1):G470-5 [1996c]).

Another factor thought to contribute to satiety is glucagon-likepeptide-1 (7-36) amide (GLP-1), which is processed from proglucagon inthe distal ileum as well as in the central nervous system. In theperiphery, GLP-1 acts as an incretin factor (inducer of insulinsecretion) and profoundly inhibits upper gastrointestinal motility(e.g., ileal brake), the latter function presumably involving thecentral nervous system (Turton, M. D. et al., A role for glucagon-likepeptide-1 in the central regulation of feeding, Nature 379(6560):69-72[1996]; Dijk, G. and Thiele, T. E., Glucagon-like peptide-1 (7-36)amide: a central regulator of satiety and interoceptive stress,Neuropeptides 33(5):406-414 [1999]). Within the central nervous system,GLP-1 has a satiating effect, since administration of GLP-1 into thethird cerebral ventricle reduces short-term food intake (and meal size),while administration of GLP-1 antagonists have the opposite effect(Dijk, G. and Thiele [1999]; but see, Asarian, L. et al.,Intracerebroventicular glucagon-like peptide-1 (7-36) amide inhibitssham feeding in rats without eliciting satiety, Physiol. Behav.64(3):367-72 [1998]). Lactate is another putative satiety factor.(Silberbauer, C. J. et al., Prandial lactate infusion inhibitsspontaneous feeding in rats, Am. J. Physiol. Regul. Integr. Comp.Physiol. 278(3):R646-R653 [2000]).

Meyer taught a method for controlling appetite involving the delivery tothe ileum of food grade nutrients, including sugars, free fatty acids,polypeptides, amino acids for controlling satiety (Meyer, J. H.,Composition and method for inducing satiety, U.S. Pat. No. 5,753,253).

Satiety can also be regulated by cytokines, such as IL-1, which isthought to operate directly on the hypothalamus or, alternatively, toincrease the synthesis of tryptophan (Laviano, A. et al., Peripherallyinjected IL-1 induces anorexia and increases brain tryptophanconcentrations, Adv. Exp. Med. Biol. 467:105-08 [1999]). Tryptophan is aprecursor of 5-HT, which is itself a peripheral satiety signal, whichhas been thought to be acting through an afferent vagal nerve pathway.(E.g., Faris P. L. et al., Effect of decreasing afferent vagal activitywith ondansetron on symptoms of bulimia nervosa: a randomised,double-blind trial, Lancet 355(9206):792-97 [2000]; Kitchener, S. J. andDourish, C. T., An examination of the behavioral specificity ofhypophagia induced by 5-HT1B, 5-HT1C and 5-HT2 receptor agonist usingthe post-prandial satiety sequence in rats, Psychopharmacology (Berl)113(3-4):369-77 [1994]; Simansky, K. J. et al., Peripheral serotonin isan incomplete signal for eliciting satiety in sham-feeding rats,Pharmacol. Biochem. Behav. 43(2):847-54 [1992]; Edwards, S. and Stevens,R., Peripherally administered 5-hydroxytryptamine elicits the fullbehavioural sequence of satiety, Physiol. Behav. 50(5):1075-77 [1991]).

There may also be some interactions between 5-HT receptor-mediatedeffects and cholecystokinin-mediated effects on satiety. (Voight, J. P.et al., Evidence for the involvement of the 5-HT1A receptor in CKKinduced satiety in rats, Nauyn Schmiedebergs Arch. Pharmacol.351(3):217-20 [1995]; Varga, G. et al., Effect of deramciclane, a new5-HT receptor antagonist, on cholecystokinin-induced changes in ratgastrointestinal function, Eur. J. Pharmacol. 367(2-3):315-23 [1999];but see, Eberle-Wang, K. and Simansky, K. J., The CKK-A receptorantagonist, devazepide, blocks the anorectic action of CKK but notperipheral serotonin in rats, Pharmacol. Biochem. Behav. 43(3):943-47[1992]). The neuropeptide hormone cholecystokinin is known to inducesatiety, inhibit gastric emptying, and to stimulate digestive pancreaticand gall bladder activity. (Blevins, J. E. et al., Brain regions wherecholecystokinin suppresses feeding in rats, Brain Res. 860(1-2):1-10[2000]; Moran, T. H. and McHugh, P. R., Cholecystokinin suppresses foodintake by inhibiting gastric emptying, Am. J. Physiol. 242(5):R491-97[1982]; McHugh, P R. and Moran, T. H. [1986]; Takahashi, H. et al.,Composition for digestion of protein, JP5246846A).

Cholecystokinin, and other neuropeptides, such as bombesin, amylin,proopiomelanocortin, corticoptropin-releasing factor, galanin,melanin-concentrating hormone, neurotensin, agouti-related protein,leptin, and neuropeptide Y, are important in the endocrine regulation ofenergy homeostasis. (Maratos-Flier, E., Promotion of eating behavior,U.S. Pat. No. 5,849,708; Inui, A., Feeding and body-weight regulation byhypthalamic neuropeptides-mediation of the actions of leptin, TrendsNeurosci. 22(2):62-67 [1999]; Bushnik, T. et al., Influence of bombesinon threshold for feeding and reward in the rat, Acta Neurobiol. Exp.(Warsz) 59(4):295-302 [1999]; Sahu, A., Evidence suggesting that galanin(GAL), melanin-concentrating hormone (MCH), neurotensin (NT),proopiomelanocotin (POMC) and neuropeptide Y (NPY) are targets of leptinsignaling in the hypothalamus, Endocrinol. 139(2):795-98 [1999]). Manyof these neuropeptides are multi-functional, binding several differentreceptors at different sites in the body. For example, neuropeptide Y(NPY), a 36-amino-acid peptide widely expressed in the brain is a potentappetite inducing signal molecule as well as a mitogen and avasoconstrictor active in cardiovascular homeostatis. (Kokot, F. andFicek, R., Effects of neuropeptide Y on appetite, Miner. ElectrolyteMetab. 25(4-6):303-05 [1999]).

Neuropeptide Y (NPY) and other neuropeptides may be involved inalternative biochemical satiety-regulating cascades within thehypothalamus. (E.g., King, P. J. et al., Regulation of neuropeptide Yrelease from hypothalamic slices by melanocortin-4 agonists and leptin,Peptides 21(1):45-48 [2000]; Hollopeter G. et al., Response ofneuropeptide Y-deficient mice to feeding effectors, Regul. Pept.75-76:383-89 [1998]). Bruno et al. taught a method of regulatingappetite and metabolism in animals, including humans, which involvesinter alia administering a composition that modulates synthesis andsecretion of neuropeptide Y. (Bruno, J. F. et al., U.S. Pat. No.6,013,622). Moreover, the neuropeptide Y-leptin endocrine axis has beenconsidered a central mechanism of satiety regulation in mammals.Neuropeptide Y and leptin have opposite effects in thearcuate-paraventricular nucleus (ARC-PVN) of the hypothalamus, withleptin being satiety-inducing and a suppressor of neuropeptide Y (andagouti-related protein) expression. (E.g., Baskin, D. G. et al., Leptinsensitive neurons in the hypothalamus, Horm. Metab. Res. 31(5):345-50[1999]). In phenotypically obese mice with an ob/ob genotype, adiposecells fail to secrete leptin, and neuropeptide Y is overexpressed in thehypothalamus. (Erickson, J. C. et al., Attenuation of the obesitysyndrome of ob/ob mice by the loss of neuropeptide Y, Science274(5293):1704-07 [1996]).

Neuropeptide Y mediates its effects through binding to Y1, Y2, Y4, andY5 G-protein-coupled receptors on the surfaces of cells of the ARC-PVNof the hypothalamus. (Naveilhan, P. et al., Normal feeding behavior,body weight and leptin response require the neuropeptide Y Y2 receptor,Nat. Med. 5(10):1188-93 [1999]; King, P. J. et al., Regulation ofneuropeptide Y release by neuropeptide Y receptor ligands and calciumchannel antagonists in hypothalamic slices, J. Neurochem. 73(2):641-46[1999]). Peptide YY can also bind to these receptors. In addition, Y1,Y2, Y4/PP1, Y5 and Y5/PP2/Y2 receptors for peptide YY are localized inmyenteric and submuscosal nerve cell bodies, endothelial cells, andendocrine-like cells of the rat intestinal tract. (Jackerott, M. et al.,Immunocytochemical localization of the NPY/PYY Y1 receptor in entericneurons, endothelial cells, and endocrine-like cells of the ratintestinal tract, J. Histochem Cytochem., 45(12):1643-50 (December1997); Mannon, P. J. et al., Peptide YY/neuropeptide Y Y1 receptorexpression in the epithelium and mucosal nerves of the human colon,Regul. Pept., 83(1):11-19 [1999]). But until now, a way of manipulatingsatiety has been unknown that exploits linkages between afferent andefferent neural pathways with the hypothalamic endocrine regulation ofsatiety and post-prandial visceral blood flow.

A treatment for visceral hyperalgesia or hypersensitivity is also adesideratum. Visceral hyperalgesia, or pain hypersensitivity, is acommon clinical observation in small intestinal bacterial overgrowth(SIBO), Crohn's disease, and irritable bowel syndrome (IBS). As many as60% of subjects with IBS have reduced sensory thresholds for rectaldistension compared to normal subjects. (H. Mertz et al., Altered rectalperception is a biological marker of patients with the irritable bowelsyndrome, Gastroenterol. 109:40-52 [1995]). While the experience of painis intertwined with a person's emotions, memory, culture, andpsychosocial situation (D. A. Drossman and W. G. Thompson, Irritablebowel syndrome: a graduated, multicomponent treatment approach, Ann.Intern. Med. 116:1009-16 [1992]) and the etiology for this hyperalgesiahas remained elusive, evidence shows that certain cytokinemediated-immune responses can influence the perception of pain.Cytokines, including IL-1(α and β), IL-2, IL-6, and TNF-α, can bereleased in response to a variety of irritants and can modulate theperception of pain, possibly through the mediation of kinin B₁ and/or B₂receptors (see, M. M. Campos et al., Expression of B ₁ kinin receptorsmediating paw oedema formalin-induced nociception. Modulation byglucocorticoids, Can. J. Physiol. Pharmacol. 73:812-19 [1995]; R. O. P.de Campos et al., Systemic treatment with Mycobacterium bovis bacilluscalmett-guerin (BCG) potentiates kinin B ₁ receptor agonist-inducednociception and oedema formation in the formalin test in mice,Neuropeptides 32(5):393-403 [1998]). Cytokine and neuropeptide levelsare altered in IBS. An increase in substance P (neuropeptide)-sensitivenerve endings has been observed in subjects with IBS. (X. Pang et al.,Mast cell substance P-positive nerve involvement in a patient with bothirritable bowel syndrome and interstitial cystitis, Urology 47:436-38[1996]). It has also been hypothesized that there is a sensitization ofafferent pathways in IBS. (E. A. Mayer et al., Basic and clinicalaspects of visceral hyperalgesia, Gastroenterol 1994; 107:271-93 [1994];L. Bueno et al., Mediators and pharmacology of visceral sensitivity:from basic to clinical investigations, Gastroenterol. 112:1714-43[1997]).

In summary, a need exists for manipulating upper gastrointestinaltransit and post-prandial visceral blood flow, by which absorption ofingested nutrients and/or drugs in the small intestine can be optimizedto prevent and/or reduce ineffectiveness thereof due to malabsorptionand to enhance the bioavailability and effectiveness of drugs. A needalso exists to manipulate satiety and to treat visceral hyperalgesia, bywhich optimal nutritional intake and visceral comfort can be achieved.Through a unifying conception of visceral neural regulatory pathways,the present invention satisfies these needs and provides relatedadvantages as well.

SUMMARY OF THE INVENTION

The present invention takes advantage of a novel understanding of theperipheral neural connections that exist between the enteric nervoussystem of the upper gastrointestinal tract, including an intrinsicserotonergic neural pathway, and the vertebral ganglia, and thence tothe central nervous system. The present invention provides a means toenhance region-to region (e.g., gut-to-CNS or gut-to gut) communicationsby way of replicating 5-HT as a signal (or releasing 5-HT at a distanceas a surrogate signal). Thus, the present invention provides a way toincrease 5-HT in locations in the central nervous by transmitting aneural signal from the gut, or to transmit a 5-HT-mediated neural signaloriginating in one location in the gut via an intrinsic cholinergicafferent neural pathway to a second distant location in the gut where aserotonergic signal of the same or greater intensity is replicated.

The present technology, therefore, allows bi-directional neurallymediated modulation of the rate of upper gastrointestinal transit,feelings of satiety, visceral pain perception, and post-prandialvisceral blood flow in a mammalian subject, such as a human. The presentinvention allows the artificially directed transmission and/oramplification of nervous signals from one location in the entericnervous system to another via a prevertebral ganglion, bypassing thecentral nervous system, or alternatively to artificially direct nervoussignal transmission from the enteric nervous system to the centralnervous system, including the hypothalamus, and back again.

The invention takes advantage of an intrinsic serotonergic neuralpathway involving an intrinsic cholinergic afferent neural pathway thatprojects from peptide YY-sensitive primary sensory neurons in theintestinal wall to the prevertebral celiac ganglion. The prevertebralceliac ganglion is in turn linked by multiple prevertebral ganglionicpathways to the central nervous system, to the superior mesentericganglion, to the inferior mesenteric ganglion, and also back to theenteric nervous system via an adrenergic efferent neural pathway thatprojects from the prevertebral celiac ganglion to one or moreenterochromaffincells in the intestinal mucosa and to serotonergicinterneurons that are, in turn, linked in the myenteric plexus orsubmucous plexus to opioid interneurons. The opioid interneurons are inturn linked to excitatory and inhibitory motoneurons. The opioidinterneurons are also linked by an intestino-fugal opioid pathway thatprojects to the prevertebral celiac ganglion, with one or more neuralconnections therefrom to the central nervous system, including thespinal cord, brain, hypothalamus, and pituitary, and projecting backfrom the central nervous system to the enteric nervous system.

In particular, the present invention includes a method of manipulatingthe rate of upper gastrointestinal transit of a substance in a mammal,whether the substance be a food or drug. The method involvesadministering by an oral or enteral delivery route a pharmaceuticallyacceptable composition comprising an active agent to the mammal's uppergastrointestinal tract. Depending on the desired results, the activeagent to be selected can be an active lipid; a serotonin, serotoninagonist, or serotonin re-uptake inhibitor; peptide YY or a peptide YYfunctional analog; calcitonin gene-related peptide or a functionalanalog thereof; an adrenergic agonist; an opioid agonist; a combinationof any of any of these; or an antagonist of a serotonin receptor,peptide YY receptor, adrenoceptor, opioid receptor, and/or calcitoningene-related peptide (CGRP) receptor.

If it is desired to slow the rate of upper gastrointestinal transit, theactive agent is an active lipid; a serotonin, serotonin agonist, orserotonin re-uptake inhibitor; peptide YY or a peptide YY functionalanalog; CGRP or a CGRP functional analog; an adrenergic agonist; anopioid agonist; or a combination of any of any of these, which isdelivered in an amount and under conditions such that the cholinergicintestino-fugal pathway, at least one prevertebral ganglionic pathway,the adrenergic efferent neural pathway, the serotonergic interneuronand/or the opioid interneuron are activated thereby. This is also thebasis for the inventive method for prolonging the residence time of anorally or enterally administered substance by promoting its dissolution,bioavailability and/or absorption in the small intestine.

Alternatively, if it is desired to accelerate the rate of uppergastrointestinal transit, then an antagonist of a serotonin receptor,peptide YY receptor, adrenoceptor, opioid receptor, CGRP receptor, or acombination of any of these is delivered in an amount and underconditions such that the cholinergic intestino-fugal pathway, at leastone prevertebral ganglionic pathway, the adrenergic efferent neuralpathway, the serotonergic interneuron and/or the opioid interneuron areblocked thereby.

The invention also includes a method of manipulating satiety in amammalian subject. The method involves administering a pharmaceuticallyacceptable composition comprising an active agent by an oral or enteraldelivery route to the mammal's upper gastrointestinal tract. Dependingon the desired results, the active agent to be selected can be an activelipid; a serotonin, serotonin agonist, or serotonin re-uptake inhibitor;peptide YY or a peptide YY functional analog; CGRP or a CGRP functionalanalog; an adrenergic agonist; an opioid agonist; a combination of anyof any of these; or an antagonist of a serotonin receptor, peptide YYreceptor, CGRP receptor; adrenoceptor and/or opioid receptor. If it isdesired to induce a feeling of satiety in the subject, for example incases of obesity, the active agent is an active lipid; a serotonin,serotonin agonist, or serotonin re-uptake inhibitor; peptide YY or apeptide YY functional analog; calcitonin gene-related peptide or afunctional analog; CGRP or a CGRP functional analog; an adrenergicagonist; an opioid agonist; or a combination of any of these, which isdelivered in an amount and under conditions such that the cholinergicintestino-fugal pathway, at least one prevertebral ganglionic pathway,the adrenergic efferent neural pathway, the serotonergic interneuronand/or the opioid interneuron are activated thereby.

If it is desired to suppress satiety in the subject, for example incases of wasting such as are seen among cancer patients, the activeagent is an antagonist of a serotonin receptor, peptide YY receptor, aCGRP receptor; an adrenoceptor, opioid receptor, or a combination of anyof these receptor antagonists, delivered in an amount and underconditions such that the cholinergic intestino-fugal pathway, at leastone prevertebral ganglionic pathway, the adrenergic efferent neuralpathway, the serotonergic interneuron and/or the opioid interneuron areblocked thereby.

Similarly, an inventive method of treating visceral pain or visceralhypersensitivity in a human subject method involves administering anactive agent by an oral or enteral delivery route to human subject. Theactive agent is selected from among antagonists of serotonin receptors;peptide YY receptors; CGRP receptors; adrenoceptors; and opioidreceptors, and is delivered in an amount and under conditions such thatactivation of a cholinergic intestino-fugal pathway, prevertebralganglionic pathways, gangalion to central nervous system pathways, theadrenergic efferent neural pathway, the serotonergic interneuron and/orthe opioid interneuron is blocked by the action of the active agent. Thesensation of esophageal, gastric, biliary, intestinal, colonic or rectalpain experienced by the human subject is thereby reduced. The method isof benefit, for example, in treating some irritable bowel syndrome (IBS)patients who experience visceral pain and/or hypersensitivity.

The present invention further provides methods and pharmaceuticallyacceptable compositions for enhancing the bioavailability andtherapeutic effectiveness of drugs.

These and other advantages and features of the present invention will bedescribed more fully in a detailed description of the preferredembodiments which follows. In further describing the invention, thedisclosures of related applications U.S. Ser. Nos. 09/420,046;09/359,583; 08/832,307 and 08/442,843 are incorporated by reference.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 demonstrates that slowing of the rate of intestinal transit byfat depends on peptide YY (PYY), which is a physiological fat signalmolecule.

FIG. 2 demonstrates that demonstrates that slowing of the rate ofintestinal transit by fat depends on a serotonergic pathway.

FIG. 3 illustrates that the fat induced ileal brake depends on anondansetron-sensitive, efferent serotonin (5-HT)-mediated pathway.

FIG. 4 shows that ondansetron abolishes the fat-induced ileal brake in adose-dependent fashion.

FIG. 5 shows that ondansetron abolishes the fat-induced ileal brake whenadministered luminally but not intravenously.

FIG. 6 illustrates that the slowing of intestinal transit by distal gut5-HT depends on an ondansetron-sensitive 5-HT-mediated pathway in theproximal (efferent) and distal (afferent) gut.

FIG. 7 illustrates that slowing of intestinal transit by distal gut fatdepends on an extrinsic adrenergic neural pathway.

FIG. 8 illustrates that slowing of intestinal transit by PYY depends onan extrinsic adrenergic neural pathway.

FIG. 9 illustrates that slowing of intestinal transit by 5-HT in thedistal gut depends on an extrinsic adrenergic neural pathway.

FIG. 10 illustrates that intestinal transit is slowed by norepinephrine(NE) in a 5-HT-mediated neural pathway.

FIG. 11 illustrates that the fat-induced jejunal brake depends on theslowing effect of a naloxone-sensitive, opioid neural pathway.

FIG. 12 illustrates that the fat-induced ileal brake depends on theslowing effect of an efferent, naloxone-sensitive, opioid neuralpathway.

FIG. 13 shows that slowing of intestinal transit by distal gut 5-HTdepends on a naloxone-sensitive, opioid neural pathway.

DETAILED DESCRIPTION OF THE INVENTION

The upper gastrointestinal tract includes the entire alimentary canal,except the cecum, colon, rectum, and anus. While some digestiveprocesses, such as starch hydrolysis, begin in the mouth and esophagus,of particular importance as sites of digestion are the stomach and smallintestine, which includes the duodenum, jejunum, and the ileum.Important steps in dietary lipid absorption begin in the stomach, wherean intricate control system of inhibitory and stimulatory motilitymechanisms are set in motion by the composition of the meal ingested.These mechanisms prevent too rapid emptying of gastric contents into theduodenum, which would overwhelm its capacity for lipid or fatabsorption. Such preventative mechanisms ensure a maximum interface ofthe water-insoluble lipid with the aqueous contents of the intestinaltract.

The next step in absorption of fats or lipids (terms used hereininterchangeably) occurs upon their entry into the small intestine. Inthe early portion of the small intestine, specific receptors for fatsand proteins, and the osmolality, acidity and the particle size of themeal activate propulsive and inhibitory reactions (i.e., ileal braking),which modulate their transit and absorption. The rate of passage throughthe small intestine (i.e., intestinal transit time) is of greatsignificance for the rate and extent of absorption from the smallintestine.

In the duodenum, the fats which have been released from the stomachencounter bile acids and pancreatic enzymes. The function of the bileacids is to render soluble the insoluble triglyceride molecules.

The intestinal absorption of lipids is normally very efficient over wideranges of dietary fat intake. A normal person generally absorbsapproximately 95-98% of dietary lipid. When the normal digestive andabsorptive processes are impaired, malabsorption syndromes frequentlyensue. The inventive method of manipulating upper gastrointestinaltransit is useful for optimizing the digestive and absorptive processesfor any individual mammal, including humans, and excepting ruminantssuch as camels, deer, antelopes, goats, sheep, and cattle. Malabsorptionsyndromes include a large heterogeneous group of gastrointestinaldisorders with the common characteristic of failure to assimilateingested substances normally. The defect is characterized by decreasedor impaired function of almost any organ of the gut, including theliver, biliary tract, pancreas, and lymphatic system, as well as theintestine. The clinical manifestations can vary from a severe symptomcomplex of rapid intestinal transit, dumping syndrome, diarrhea, weightloss, distention, steatorrhea, and asthenia to symptoms of specificnutrient deficiencies (i.e., malnutrition).

Examples of gastrointestinal disorders that frequently manifest as oneor more malabsorption syndromes are postgastrectomy syndrome, dumpingsyndrome, AIDS-associated chronic diarrhea, diabetes-associateddiarrhea, postvagotomy diarrhea, bariatric surgery-associated diarrhea(including obesity surgeries: gastric bypass, gastroplasties andintestinal bypass), short bowel syndrome (including resection of thesmall intestine after trauma, radiation induced complications, Crohn'sdisease, infarction of the intestine from vascular occlusion),tube-feeding related diarrhea, chronic secretory diarrhea, carcinoidsyndrome-associated diarrhea, gastrointestinal peptide tumors, endocrinetumors, chronic diarrhea associated with thyroid disorders, chronicdiarrhea in bacterial overgrowth, chronic diarrhea in gastrinoma,choleraic diarrhea, chronic diarrhea in giardiasis,antibiotic-associated chronic diarrhea, diarrhea-predominant irritablebowel syndrome, chronic diarrhea associated with maldigestion andmalabsorption, chronic diarrhea in idiopathic primary gastrointestinalmotility disorders, chronic diarrhea associated with collagenouscolitis, surgery-associated acute diarrhea, antibiotic-associated acutediarrhea, infection-associated acute infectious diarrhea, and the like.

The rate at which food passes through the gastrointestinal tract is animportant factor that affects the absorptive capacity and the outcomefollowing gastric surgery and/or intestinal resection. Resection ofextensive sections of bowel as well as loss of absorptive surfacesecondary to diseased small bowel mucosa can lead to specificmalabsorption syndromes. Resection or disease of large amounts ofterminal ileum are known to cause vitamin B12 and bile aciddeficiencies, which, in turn, can lead to fat and other fat-solublesubstances being less well absorbed. Bypassed loops of bowel, created byeither surgery or fistula formation, and strictures can result in blindloop syndromes with bacterial overgrowth and subsequent malabsorption.Malnutrition is a common problem in patients with inflammatory boweldiseases such as, for example, Crohn's disease or ulcerative colitis.Weight loss is found in 70-80% of patients with Crohn's disease and18-62% of patients with ulcerative colitis.

The role of nutritional support as a primary therapy for inflammatorybowel diseases is not well established. Given the natural history ofinflammatory bowel diseases, with frequent relapses and spontaneousremissions, and the difficulty and variability in quantifying diseaseactivity, it has been difficult to design clinical trials thatdefinitively establish the role of nutrition as a primary therapy forinflammatory bowel diseases. The use of elemental diets as primarytherapy for inflammatory bowel diseases has also been examined.Parenteral nutrition and elemental diets appear to have limited roles inthe long-term treatment of patients with inflammatory bowel diseases.

Short bowel syndrome generally refers to a condition in which less than150 cm of remaining small bowel is associated with a massive loss ofabsorptive capacity. It is characterized by severe diarrhea andmalabsorption. Patients with short bowel syndrome often experiencemalabsorption of protein, carbohydrate and fat resulting in caloriedepletion and steatorrhea.

The most important therapeutic objective in the management of shortbowel is to maintain the patient's nutritional status. By necessity, itis achieved primarily by parenteral nutrition support in the earlypostoperative period. Enteral nutrition support can be started earlyafter operation when the ileus has resolved. Maximization of enteralabsorption of nutrients is important for long-term survival. Generally,such maximization requires that the enteral intake greatly exceed theabsorptive needs to ensure that the nutritional requirements are met.Functional pancreatic insufficiency can also cause steatorrhea aftergastric resection. Steatorrhea is the presence of excess fat in thefeces. It is usually caused by a defect in gastrointestinal digestionand/or absorption. Steatorrhea rarely exists without malabsorption ofother substances. For example, conditions such as osteomalacia relatedto calcium and vitamin D deficiency or anemia due to selective iron orB12 deficiencies are often associated with the malabsorption that occurswith steatorrhea. Weight loss occurs because of a loss of nutrients andenergy. Diarrhea is another major symptom associated with steatorrhea.It is present in 80-97% of patients with malabsorption.

Dumping syndrome is one of the most common causes of morbidity aftergastric surgery. This syndrome is characterized by both gastrointestinaland vasomotor symptoms. Gastrointestinal symptoms include postprandialfullness, crampy abdominal pain, nausea, vomiting and explosivediarrhea. Vasomotor symptoms include diaphoresis, weakness, dizziness,flushing, palpitations, and an intense desire to lie down. Patients withsevere dumping symptoms may limit their food intake to minimize symptomsand as a result lose weight and become malnourished. In severe cases, asa last resort surgical treatment of dumping syndrome has been utilized.

Pharmaceutical treatment for severe dumping includes octreotide acetate(Sandoz), a long acting somatostatin analogue, which has been used withsome success. Octreotide is administered subcutaneously and acts to slowgastric emptying, inhibit insulin release, and decrease enteric peptidesecretion. Octreotide, unfortunately, is accompanied by severalcomplications, which include injection site pain, tachyphylaxis,iatrogenic diabetes, malabsorption and cholelithiasis.

Diarrhea is a common problem after any abdominal operation. Treatmentincludes simple dietary changes, opiates and/or opioid-type drugs suchas Lomotil or paregoric, antidiarrheal agents such as Diasorb(attapulgite), Donnagel (kaolin, hydroscyamine sulfate, atropine sulfateand scopalamine hydrobromide), Kaopectate, Motofen (difenoxinhydrochloride and atropine sulfate) and Pepto-Bismol for inhibitoryeffect on intestinal transit. Each modality of treatment, however, hashad limited success and with the exception of dietary changes, all havenegative side effects associated with use.

Diarrhea is a common problem in motility disorders of thegastrointestinal tract, such as in diarrhea-predominant irritable bowelsyndrome, small intestinal bacterial overgrowth and diabetes.

Diarrhea is also a common complication associated with enteral feeding.Multiple etiologies for diarrhea are postulated, and its genesis may bea multifactorial process (Edes et al., Am. J. Med. 88:91-93 (1990).Causes include concurrent use of antibiotics or other diarrhea-inducingmedications, altered bacterial flora, formula composition, rate ofinfusion, hypoalbuminemia, and enteral formula contamination. Thecomposition of formula can also affect the incidence of diarrhea. Theuse of fiber-containing formulas to control diarrhea related to tubefeeding is unsettled (Frankenfield et al., Am. J. Clin. Nutr. 50:553-558[1989]).

Ileus or bowel obstruction are common complications associated with thelong-term administration of opioid drugs such as morphine, heroin,opium, codeine, or methadone. In addition, ileus is a commonpost-operative complication that often prevents the resumption offeeding.

Satiety encompasses a lack of appetite for food or a cessation offood-seeking or food-ingesting behavior. Thus, satiety is a desirablestate in conditions in which food intake is preferably curtailed, suchas obesity. Alternatively, it can be desirable to suppress a state ofsatiety in conditions of anorexia or cachexia resulting from causesincluding illness, starvation, or chemotherapy.

Visceral hyperalgesia encompasses excessive or abnormal sensitivity tovisceral sensations that are not normally consciously perceived,including hypersensitivity approaching a level of discomfort or pain.Visceral hyperalgesia is a common feature of SIBO, IBS, or Crohn'sdisease, which can severely impinge on a person's quality of life andnutritional state.

Techniques such as Doppler utrasonography and phase-contrast magneticresonance imaging have made it possible to record blood flow to thegastrointestinal tract through the superior mesenteric artery directlyand continuously in unanaesthetized, healthy humans. Several researchgroups have demonstrated how blood flow to the gastrointestinal tractincreases gradually and markedly after a meal, and more so after a bigmeal than after a small one. The increase in post-prandial blood flowreaches its maximum after 20-40 minutes and lasts for 1.5-2 hours. Inthe postprandial period there is a parallel and similar increase incardiac output; the meal thus imposes an increased work load on theheart.

The normal postprandial response is important to effective digestion andnutrient absorption. However, abnormally low postprandial visceral bloodflow is a common complication of conditions such as insulin resistancein adults or of phototherapy in infants. (E.g., Summers, L. K. et al.,Impaired post-prandial tissue regulation of blood flow in insulinresistance: determinant of cardiovascular risk?, Atherosclerosis147(1):11-15 [1999]; Pezatti, M. et al., Changes in mesenteric bloodflow response to feeding: conventional versus fiber-optic phototherapy,Pediatrics 105(2):350-53 [2000]). On the other hand, abnormallyincreased visceral or gastrointestinal blood flow is a feature ofulcerative colitis and cirrhosis, which at the very least placesabnormal stress on the heart. (E.g., Ludwig, D. et al., Mesenteric bloodflow is related to disease activity and risk of relapse in ulcerativecolitis: a perspective follow-up study, Gut 45(4):546-52 [1999]; Sugano,S. et al., Azygous venous blood flow while fasting, postprandially,after endoscopic variceal ligation, measured by magnetic resonanceimaging, J. Gastroenterol. 34(3):310-14 [1999]). The present inventionprovides a method of manipulating post-prandial visceral blood flow tooptimize digestion and absorption and treat other pathologicalcomplications related to abnormal blood flow.

A tremendous amount of research has been undertaken in attempting toelucidate the role of nutrition and absorption in gastrointestinaldisorders. Despite this research, few standards of care presently existfor the use of nutrition and absorption in most aspects of thesedisorders.

Accordingly, the present invention provides a method of manipulatingupper gastrointestinal transit, whether to slow it to prolong theresidence time of a substance in the small intestine of a subject for anamount of time sufficient for digestion and absorption of the substanceto occur therein, or whether to accelerate upper gastrointestinaltransit, for example, in subjects experiencing delayed transit resultingfrom the administration of opioid medications.

In order to optimally digest and absorb fat, intestinal transit isslowed by this nutrient in a dose-dependent fashion as the fat-inducedjejunal brake (Lin, H. C. et al. [1996a]) and ileal brake (Lin, H. C. etal., Intestinal transit is more potently inhibited by fat in the distal[ileal] brake than in the proximal [jejunal] brake, Dig. Dis. Sci.42:19-25 [1996d]). To achieve these responses, the sensory nerves of thesmall intestine must detect and respond to the fat in the intestinallumen. Sensory nerves that respond specifically to the presence of fatin the lumen (fat-sensitive primary sensory neurons) are found in thelamina propria, separated from the intestinal lumen by the mucosa. Sincethese fat-sensitive sensory nerves do not have access to the lumen (Mei,N., Recent studies on intestinal vagal efferent innervation. Functionalimplications, J. Auton. Nerv. Syst. 9:199-206 [1983]; Melone, J., Vagalreceptors sensitive to lipids in the small intestine of the cat, J.Auton. Nerv. Syst. 17:231-241 [1986]), one or more intermediary signalsmust be available. PYY is a signal for fat (Lin, H. C. et al., Slowingof intestinal transit by fat in proximal gut depends on peptide YY,Neurogastroenterol. Motility 10:82 [1998]; Lin, H. C. et al. [1996b])and is released in response to fat in the lumen of the can or distalgut. Intestinal cells such as those that release PYY, do have directaccess to the luminal content and serve as an intermediarysignal-transmitting link between luminal fat and the fat-sensitiveprimary sensory neurons in the lamina propria.

Serotonin or 5-hydroxytryptamine (5-HT) from enterochromaffin cells(ECC) also has this signaling role. 5-HT is also produced byserotonergic interneurons of the myenteric plexus (Gershon, M. D., Theenteric nervous system, Annu. Rev. Neurosci. 4:227-272 [1981]; Gershon,M. D. et al., Serotonin: synthesis and release from the myenteric plexusof the mouse intestine, Science 149:197-199 [1965]; Holzer, P. andSkotfitsch, G., Release of endogenous 5-hydroxytryptamine from themyenteric plexus of the guinea-pig isolated small intestine, Br. J.Pharmacol. 81:381-86 [1984]).

In addition to mediating neural signal transmission in the intrinsicserotonergic neural pathway, the release of 5-HT can occur as a resultof activation of an extrinsic neural pathway consisting of a cholinergicafferent nerve and an adrenergic efferent nerve (Kunze, W. A. et al.,Intracellular recording of from myenteric neurons of the guinea-pigileum that responds to stretch, J. Physiol. 506:827-42 [1998]; Smith, T.K. and Furness, J. B., Reflex changes in circular muscle activityelicited by stroking the mucosa: an electrophysiological analysis in theisolated guinea-pig ileum, J. Auton. Nerv. Syst. 25:205-218 [1988]).Although the location of this extrinsic neural pathway is currentlyunknown, the extrinsic nerves going back and forth between the gut andthe prevertebral ganglia (Bayliss, W. M. and Starling, E. H., Themovement and innervation of the small intestine, J. Physiol. 24:99[1899], Kosterlitz, H. W. and Lees, G. M., Pharmacological analysis onintrinsic intestinal reflexes, Pharmacol. Rev. 16:301-39 [1964];Kuemmerle, J. F. and Makhlouf, G. M., Characterization of of opioidreceptors in intestinal muscle cells by selective radioligands andreceptor protection, Am. J. Physiol. 263:G269-G276 [1992]; Read, N. W.et al., Transit of a meal through the stomach, small intestine, andcolon in normal subjects and its role in the pathogenesis of diarrhea,Gastroenterol. 79:1276-82 [1980]) are likely candidates since thesenerves allow different regions of the gut to communicate and alsoconsist of a cholinergic afferent and an adrenergic efferent. Inaccordance with the inventive methods, the release of 5-HT by a signalprojecting from one part of the intestine to another via extrinsicnerves provides a relay mechanism for the slowing of transit through theproximal gut by the fat-induced ileal brake or through the distal gut bythe fat-induced jejunal brake.

The pharmaceutically acceptable composition comprises the active agent,and is formulated to deliver the active agent to a desired section ofthe upper gastrointestinal tract. The inventive pharmaceuticallyacceptable compositions also comprise a pharmaceutically acceptablecarrier. Optionally, a drug or other substance to be absorbed can beincluded in the same composition, or alternatively can be provided in aseparate formulation.

In some preferred embodiments, the pharmaceutically acceptablecomposition includes the active agent in a dose and in a form effectiveto prolong the residence time of an orally or enterally administeredsubstance by slowing the transit of the substance through the smallintestine for an amount of time sufficient for absorption of saidsubstance to occur therein.

The invention contemplates a range of optimal residence times which aredependent upon the character of the substance (i.e., nutrients, drugs).As used herein, “substance” encompasses the lumenal content of thegastrointestinal tract which includes, for example, digested andpartially digested foods and nutrients, dissolved and/or solubilizeddrugs as well as incompletely dissolved and/or solubilized formsthereof, electrolyte-containing lumenal fluids, and the like.

The small intestinal residence time for optimal absorption of digestedfoods and nutrients can be calculated using an average orocecal transittime as a reference. The normal orocecal transit time is approximately2-3 hours in the fasted state. The inventive composition should targetan intestinal residence within the same average time frame ofapproximately 2-3 hours.

The pharmaceutical industry has published a great deal of information onthe dissolution time for individual drugs and various compounds. Suchinformation is found in the numerous pharmacological publications whichare readily available to those of skill in the art. For example, if thein vitro model for dissolution and release of drug “X” is 4 hours, thenthe small intestinal residence time for optimal absorption of drug “X”would be at least 4 hours and would also include additional timeallowing for gastric emptying to occur in vivo. Thus, for drugs, theappropriate residence time is dependent on the time for release of thedrug.

As used herein, “digestion” encompasses the process of breaking downlarge molecules into their smaller component molecules.

As used herein, “absorption” encompasses the transport of a substancefrom the intestinal lumen through the barrier of the mucosal epithelialcells into the blood and/or lymphatic systems.

As used herein, a drug is a chemotherapeutic or other substance used totreat a disorder, abnormal condition, discomfort, wound, lesion, orinjury, of a physical, biochemical, mental, emotional or affectivenature. Examples of drugs include, but are not limited to, somatostatinanalogues, insulin release inhibitors, anti-diarrheal agents,antibiotics, fiber, electrolytes, analgesics, antipyretics, migrainetreatment, migraine prophylaxis, antifungal agents, antiviral agents,Quinolones, AIDS therapeutic agents, anti-infectives, aminoglycosides,antispasmodics, parasympathomimetics, anti-tuberculous agents,anti-malarial agents, accines, anti-parasitic agents, cephalosporins,macrolides, azalides, tetracyclines, penicillins, anti-arthritic therapyagents, gout therapy agents, nonsteroidal anti-inflammatory agents, goldcompounds, antianemic agents, antianginal agents, antiarrhythmics,anticoagulants, post-MI agents, vasodilators, beta-adrenergic blockers,calcium channel blockers, nitrates, thrombolytic agents, anticoagulants,antifibrolytic agents, hemorrheologic agents, antiplatelet agents,vitamins, antihemophilic agents, heart failure agents, ACE inhibitors,cardiac glycosides, blood flow modifying agents, bile salts, growthpromoting agents, growth suppressive agents, sympathomimetics, inotropicagents, antihypertensive agents, central alpha-adrenergic agonists,peripheral vasodilator, sympatholytics, diuretics, diureticcombinations, mineral supplements, hypolipedemic agents, acnetreatments, antidiarrheal agents, antinauseants, antiemetics,antispasmodics, antiulcer, antireflux agents, appetite suppressants,appetite enhancers, gallstone-dissolving agents, gastrointestinalanti-inflammatory agents, antacids, antiflatulents, anti-gas agents,laxatives, stool softeners, digestants, digestive enzymes, enzymesupplements, Alzheimer's therapy, anticonvulsants, antiparkinson agents,sedatives, benzodiazepines, benzodiazepine receptor antagonists,receptor agonists, receptor antagonists, interferons, immunosuppressivetherapy, immunomodulatory agents, muscle relaxants, hypnotics,antianxiety agents, antimanic agents, antidepressants (e.g., tricyclicantidepressants, such as amitryptaline (Elavil); tetracyclicantidepressants, such as maprotiline; serotonin re-uptake inhibitors,such as Prozac or Zoloft; monoamine oxidase inhibitors, such asphenelzine; and miscellaneous antidepressants, such as trazadone,venlafaxine, mirtazapine, nefazodone, or bupropion [Wellbutrin]),antiobesity agents, behavior modifiers, psychostimulants,neurostimulants, abuse deterrents, anxiolytics (e.g., benzodiazepinecompounds, such as Librium, Atavin, Xanax, Valium, Tranxene, and Serax,or other anxiolytic agents such as Paxil), antipsychotics,antianaphylactic agents, antihistamines, antipruritics,anti-inflammatory agents, bronchodilators, antiasthmatic agents, cysticfibrosis therapy agents, mast-cell stabilizers, steroids, xanthines,anticholinergic agents, bioactive peptides, polypeptides, hormones,drugs acting at neuroeffector junctional sites, prostaglandins,narcotics, hypnotics, alcohols, psychiatric therapy agents, anti-cancerchemotherapy agents, drugs affecting motility, oral hypoglycemics,androgens, estrogens, nutriceuticals, herbal medications, insulin,serotonin receptor agonist, serotonin receptor antagonists, alternativemedicines, amino acids, dietary supplements, analeptic agents,respiratory agents, cold remedies, cough suppressants, antimycotics,bronchodilators, constipation aids, contraceptives, decongestants,expectorants, motion sickness products, homeopathic preparations.

In one preferred embodiment, a major function of the inventivecompositions is to slow gastrointestinal transit and controlgastrointestinal intestinal residence time of a substance to enablesubstantial completion of lumenal and mucosal events required forabsorption of the substance to occur in the small intestine. Of equalsignificance is the function of the inventive compositions to controlthe presentation of a substance to a desired region of the smallintestine for absorption.

In another preferred embodiment, the inventive pharmaceuticallyacceptable compositions limit the presentation of a substance to theproximal region of the small intestine for absorption.

Depending on the desired results, useful active agents include, activelipids; serotonin, serotonin agonists, or serotonin re-uptakeinhibitors; peptide YY or peptide YY functional analogs; CGRP or CGRPfunctional analogs; adrenergic agonists; opioid agonists; or acombination of any of any of these; antagonists of serotonin receptors,peptide YY receptors, adrenoceptors, opioid receptors, CGRP receptors,or a combination of any of these. Also useful are antagonists ofserotonin receptors, peptide YY receptors, CGRP receptors; adrenoceptorsand/or opioid receptors.

Serotonin, or 5-hydroxytryptamine (5-HT) is preferably used at a dose of0.005-0.75 mg/kg of body mass. Serotonin agonists include HTF-919 andR-093877; Foxx-Orenstein, A. E. et al., Am. J. Physiol. 275(5 Pt1):G979-83 [1998]). Serotonin re-uptake inhibitors include Prozac orZoloft.

Serotonin receptor antagonists include antagonists of 5-HT3, 5-HT1P,5-HT1A, 5-HT2, and/or 5-HT4 receptors. Examples include ondansetron orgranisetron, 5HT3 receptor antagonists (preferred dose range of 0.04-5mg/kg), deramciclane (Varga, G. et al., Effect of deramciclane, a new5-HT receptor antagonist, on cholecystokinin-induced changes in ratgastrointestinal function, Eur. J. Pharmacol. 367(2-3):315-23 [1999]),or alosetron. 5-HT4 receptor antagonists are preferably used at a doseof 0.05-500 picomoles/kg.

Peptide YY (PYY) and its functional analogs are preferably delivered ata dose of 0.5-500 picomoles/kg. PYY functional analogs include PYY(22-36), BIM-43004 (Liu, CD. et al., J. Surg. Res. 59(1):80-84 [1995]),BIM-43073D, BIM-43004C (Litvak, D. A. et al., Dig. Dis. Sci.44(3):643-48 [1999]). Other examples are also known in the art (e.g.,Balasubramaniam, U.S. Pat. No. 5,604,203).

PYY receptor antagonists preferably include antagonists of Y4/PP1, Y5 orY5/PP2/Y2, and most preferably Y1 or Y2. (E.g., Croom et al., U.S. Pat.No. 5,912,227) Other examples include BIBP3226, CGP71683A (King, P. J.et al., J. Neurochem. 73(2):641-46 [1999]).

CGRP receptor antagonists include human CGRP(8-37) (e.g., Foxx-Orensteinet al., Gastroenterol. 111(5):1281-90 [1996]).

Adrenergic agonists include norepinephrine.

Adrenergic or adrenoceptor antagonists include β-adrenoceptorantagonists, including propranolol and atenolol. They are preferablyused at a dose of 0.05-2 mg/kg.

Opioid agonists include delta-acting opioid agonists (preferred doserange is 0.05-50 mg/kg, most preferred is 0.05-25 mg/kg); kappa-actingopioid agonists (preferred dose range is 0.005-100 microgram/kg);mu-acting opioid agonists (preferred dose range is 0.05-25microgram/kg); and episilon-acting agonists. Examples of useful opioidagonists include deltorphins (e.g., deltorphin II and analogues),enkephalins (e.g., [d-Ala(2), Gly-ol(5)]-enkephalin [DAMGO];[D-Pen(2,5)]-enkephalin [DPDPE]), dinorphins,trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl-]benzeneacetamidemethane sulfonate (U-50, 488H), morphine, codeine, endorphin, orβ-endorphin.

Opioid receptor antagonists include mu-acting opioid antagonists(preferably used at a dose range of 0.05-5 microgram/kg); kappa opioidreceptor antagonists (preferably used at a dose of 0.05-30 mg/kg); deltaopioid receptor antagonists (preferably used at a dose of 0.05-200microgram/kg); and epsilon opioid receptor antagonists. Examples ofuseful opioid receptor antagonists include naloxone, naltrexone,methylnaltrexone, nalmefene, H2186, H3116, or fedotozine, i.e., (+)-1-1[3,4,5-trimethoxy)benzyloxymethyl]-1-phenyl-N,N-dimethylpropylamine.Other useful opioid receptor antagonists are known (e.g., Kreek et al.,U.S. Pat. No. 4,987,136).

The active agents listed above are not exhaustive but ratherillustrative examples, and one skilled in the art is aware of otheruseful examples.

As used herein, “active lipid” encompasses a digested or substantiallydigested molecule having a structure and function substantially similarto a hydrolyzed end-product of fat digestion. Examples of hydrolyzed endproducts are molecules such as diglyceride, monoglyceride, glycerol, andmost preferably free fatty acids or salts thereof.

In a preferred embodiment, the active agent is an active lipidcomprising a saturated or unsaturated fatty acid. Fatty acidscontemplated by the invention include fatty acids having between 4 and24 carbon atoms.

Examples of fatty acids contemplated for use in the practice of thepresent invention include caprolic acid, caprulic acid, capric acid,lauric acid, myristic acid, oleic acid, palmitic acid, stearic acid,palmitoleic acid, linoleic acid, linolenic acid, trans-hexadecanoicacid, elaidic acid, columbinic acid, arachidic acid, behenic acideicosenoic acid, erucic acid, bressidic acid, cetoleic acid, nervonicacid, Mead acid, arachidonic acid, timnodonic acid, clupanodonic acid,docosahexaenoic acid, and the like. In a preferred embodiment, theactive lipid comprises oleic acid.

Also preferred are active lipids in the form of pharmaceuticallyacceptable salts of hydrolyzed fats, including salts of fatty acids.Sodium or potassium salts are preferred, but salts formed with otherpharmaceutically acceptable cations are also useful. Useful examplesinclude sodium- or potassium salts of caprolate, caprulate, caprate,laurate, myristate, oleate, palmitate, stearate, palmitolate, linolate,linolenate, trans-hexadecanoate, elaidate, columbinate, arachidate,behenate, eicosenoate, erucate, bressidate, cetoleate, nervonate,arachidonate, timnodonate, clupanodonate, docosahexaenoate, and thelike. In a preferred embodiment, the active lipid comprises an oleatesalt.

The active agents suitable for use with this invention are employed inwell dispersed form in a pharmaceutically acceptable carrier. As usedherein, “pharmaceutically acceptable carrier” encompasses any of thestandard pharmaceutical carriers known to those of skill in the art. Forexample, one useful carrier is a commercially available emulsion,Ensure®, but active lipids, such as oleate or oleic acid are alsodispersible in gravies, dressings, sauces or other comestible carriers.Dispersion can be accomplished in various ways. The first is that of asolution.

Lipids can be held in solution if the solution has the properties ofbile (i.e., solution of mixed micelles with bile salt added), or thesolution has the properties of a detergent (e.g., pH 9.6 carbonatebuffer) or a solvent (e.g., solution of Tween). The second is anemulsion which is a 2-phase system in which one liquid is dispersed inthe form of small globules throughout another liquid that is immisciblewith the first liquid (Swinyard and Lowenthal, “PharmaceuticalNecessities” REMINGTON'S PHARMACEUTICAL SCIENCES, 17th ed., AR Gennaro(Ed), Philadelphia College of Pharmacy and Science, 1985 p. 1296). Thethird is a suspension with dispersed solids (e.g., microcrystallinesuspension). Additionally, any emulsifying and suspending agent that isacceptable for human consumption can be used as a vehicle for dispersionof the composition. For example, gum acacia, agar, sodium alginate,bentonite, carbomer, carboxymethylcellulose, carrageenan, powderedcellulose, cholesterol, gelatin, hydroxyethyl cellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, methylcellulose, octoxynol 9,oleyl alcohol, polyvinyl alcohol, povidone, propylene glycolmonostearate, sodium lauryl sulfate, sorbitan esters, stearyl alcohol,tragacanth, xantham gum, chondrus, glycerin, trolamine, coconut oil,propylene glycol, thyl alcohol malt, and malt extract.

Any of these formulations, whether it is a solution, emulsion orsuspension containing the active agent, can be incorporated intocapsules, or a microsphere or particle (coated or not) contained in acapsule.

The pharmaceutically acceptable compositions containing the activeagent, in accordance with the invention, is in a form suitable for oralor enteral use, for example, as tablets, troches, lozenges, aqueous oroily suspensions, dispersible powders or granules, emulsions, hard orsoft capsules, syrups, elixirs or enteral formulas. Compositionsintended for oral use are prepared according to any method known to theart for the manufacture of pharmaceutical compositions. Compositions canalso be coated by the techniques described in the U.S. Pat. Nos.4,256,108; 4,160,452; and 4,265,874, to form osmotic therapeutic tabletsfor controlled release. Other techniques for controlled releasecompositions, such as those described in the U.S. Pat. Nos. 4,193,985;and 4,690,822; 4,572,833 can be used in the formulation of the inventivepharmaceutically acceptable compositions.

An effective amount of active lipid is any amount that is effective toslow gastrointestinal transit and control presentation of a substance toa desired region of the small intestine. For example, an effectiveamount of active lipid, as contemplated by the instant invention, is anyamount of active lipid that can trigger any or all of the followingreflexes: intestino-lower esophageal sphincter (relaxation of LES);intestino-gastric feedback (inhibition of gastric emptying);intestino-intestinal feedback (ileo-jejunal feedback/ileal brake,jejuno-jejunal feedback/jejunal brake, intestino-CNS feedback (forexample, intensifying intestinal signalling of satiety′);intestino-pancreatic feedback (control of exocrine enzyme output);intestino-biliary feedback (control of bile flow); intestino-mesentericblood flow feedback (for the control of mucosal hyperemia);intestino-colonic feedback (so called gastro-colonic reflex whereby thecolon contracts in response to nutrients in the proximal smallintestine).

Methods of administering are well known to those of skill in the art andinclude most preferably oral administration and/or enteraladministration. Representative methods of administering include giving,providing, feeding or force-feeding, dispensing, inserting, injecting,infusing, perfusing, prescribing, furnishing, treating with, taking,swallowing, eating or applying. Preferably the pharmaceuticallyacceptable composition comprising the active agent is administered inthe setting of a meal, i.e., along with or substantially simultaneouslywith the meal, most preferably an hour or less before the meal. It isalso useful to administer the active agent in the fasted state,particularly if the pharmaceutical composition containing the activeagent is formulated for long acting or extended release. In someembodiments, such as the inventive method for manipulating post-prandialblood flow, the pharmaceutical composition is also usefully administeredup to an hour after a meal, and most preferably within one hour beforeor after the meal.

In order to stretch biologic activity so that one has a convenient,daily dosage regimen, the present invention contemplates that theinventive compositions can be administered prior to ingestion of thefood, nutrient and/or drug.

In a preferred embodiment, the inventive compositions (depending on theformulation) are administered up to a period of 24 hours prior toingestion of the food, nutrient and/or drug, but most preferably betweenabout 60 to 5 minutes before ingestion. The period of time prior toingestion is determined on the precise formulation of the composition.For example, if the formulation incorporates a controlled releasesystem, the duration of release and activation of the active lipid willdetermine the time for administration of the composition. Sustainedrelease formulation of the composition is useful to ensure that thefeedback effect is sustained.

In a preferred embodiment, the pharmaceutically acceptable compositionof the invention contains an active lipid and is administered in aload-dependent manner which ensures that the dispersion of active lipidis presented to the entire length of the small intestine.

Administration is in one or more doses such that the desired effect isproduced. In some preferred embodiments, the load of active lipid perdose is from about 0.5 grams to about 2.0 grams, but can range up toabout 25 grams per dose as needed. Generally, patients respond well tothe most preferred amount of active lipid, which is in the range ofabout 1.6 to 3.2 grams. For patients who fail to respond to this doserange, a dose between 6 and 8 grams is typically effective. Sequentialdosing is especially useful for patients with short bowel syndrome orothers with abnormally rapid intestinal transit times. In thesepatients, the first preprandial administration of the active lipidoccurs in a condition of uncontrolled intestinal transit that can failto permit optimal effectiveness of the active lipid. A second (or more)preprandial administration(s) timed about fifteen minutes after thefirst or previous administration and about fifteen minutes before themeal enhances the patient's control of intestinal lumenal contents andthe effectiveness of the active lipid in accordance with the inventivemethods. Normalization of nutrient absorption and bowel controlthroughout the day, including during the patient's extended sleepinghours, is best achieved by a dietary regimen of three major meals withabout five snacks interspersed between them, including importantly, apre-bedtime snack; administration of a dose of the inventive compositionshould occur before each meal or snack as described above.

Treatment with the inventive compositions in accordance with theinventive methods can be of singular occurrence or can be continuedindefinitely as needed. For example, patients deprived of food for anextended period (e.g., due to a surgical intervention or prolongedstarvation), upon the reintroduction of ingestible food, can benefitfrom administration of the inventive compositions before meals on atemporary basis to facilitate a nutrient adaptive response to normalfeeding. On the other hand some patients, for example those withsurgically altered intestinal tracts (e.g., ileal resection), canbenefit from continued pre-prandial treatment in accordance with theinventive methods for an indefinite period. However, clinical experiencewith such patients for over six years has demonstrated that afterprolonged treatment there is at least a potential for an adaptivesensory feedback response that can allow them to discontinue treatmentfor a number of days without a recurrence of postprandial diarrhea orintestinal dumping.

The use of pharmaceutically acceptable compositions of the presentinvention in enteral feeding contemplates adding the compositiondirectly to the feeding formula. The composition can either becompounded as needed into the enteral formula when the rate of formuladelivery is known (i.e., add just enough composition to deliver the loadof active lipids). Alternatively, the composition of the invention canbe compounded at the factory so that the enteral formulas are producedhaving different concentrations of the composition and can be usedaccording to the rate of formula delivery (i.e., higher concentration ofcomposition for lower rate of delivery).

If the inventive composition were to be added to an enteral formula andthe formula is continuously delivered into the small intestine, thecomposition that is initially presented with the nutrient formula wouldbe slowing the transit of nutrients that are delivered later. Except forthe start of feeding when transit can be too rapid because theinhibitory feedback from the composition has yet to be fully activated,once equilibrium is established, it is no longer logistically an issueof delivering the composition as a premeal although the physiologicprinciple is still the same.

Before dietary fats can be absorbed, the motor activities of the smallintestine in the postprandial period must first move the output from thestomach to the appropriate absorptive sites of the small intestine. Toachieve the goal of optimizing the movement of a substance through thesmall intestine, the temporal and spatial patterns of intestinalmotility are specifically controlled by the nutrients of the lumenalcontent.

Without wishing to be bound by any theory, it is presently believed thatearly in gastric emptying, before inhibitory feedback is activated, theload of fat entering the small intestine can be variable and dependenton the load of fat in the meal. Thus, while exposure to fat can belimited to the proximal small bowel after a small load, a larger load,by overwhelming more proximal absorptive sites, can spill further alongthe small bowel to expose the distal small bowel to fat. Thus, theresponse of the duodenum to fat limits the spread of fat so that moreabsorption can be completed in the proximal small intestine and less inthe distal small intestine. Furthermore, since the speed of movement oflumenal fat must decrease when more fat enters the duodenum, in order toavoid steatorrhea, intestinal transit is inhibited in a load-dependentfashion by fat. This precise regulation of intestinal transit occurswhether the region of exposure to fat is confined to the proximal gut orextended to the distal gut.

In accordance with the present invention it has been observed thatinhibition of intestinal transit by fat depends on the load of fatentering the small intestine. More specifically, that intestinal transitis inhibited by fat in a load-dependent fashion whether the nutrient isconfined to the proximal segment of the small bowel or allowed access tothe whole gut.

As the term is commonly used in the art, the “proximal” segment of thesmall bowel, or “proximal gut”, comprises approximately the first halfof the small intestine from the pylorus to the mid-gut. The distalsegment, or “distal gut” includes approximately the second half, fromthe mid-gut to the ileal-cecal valve.

Accordingly, the present invention provides a method of slowinggastrointestinal transit in a subject having a gastrointestinaldisorder, said method comprising administering to said subject acomposition comprising an active lipid in an amount sufficient toprolong the residence time of a substance in the small intestine.

Inventive methods and compositions are useful in the management ofnutritional and absorption in subjects having a variety ofgastrointestinal symptoms such as, abnormally rapid or slow uppergastrointestinal transit, dumping syndrome, diarrhea, weight loss,distention, steatorrhea, and asthenia to symptoms of specific nutrientdeficiencies (i.e., malnutrition), cachexia, anorexia, bulimia, andobesity.

Examples of gastrointestinal disorders for which the inventive methodsand compositions are therapeutic include postgastrectomy syndrome,dumping syndrome, AIDS-associated chronic diarrhea, diabetes-associateddiarrhea, postvagotomy diarrhea, bariatric surgery-associated diarrhea(including obesity surgeries: gastric bypass, gastroplasties andintestinal bypass), short bowel syndrome (including resection of thesmall intestine after trauma, radiation induced complications, Crohn'sdisease, infarction of the intestine from vascular occlusion),tube-feeding related diarrhea, chronic secretory diarrhea, carcinoidsyndrome-associated diarrhea, gastrointestinal peptide tumors, endocrinetumors, chronic diarrhea associated with thyroid disorders, chronicdiarrhea in bacterial overgrowth, chronic diarrhea in gastrinoma,choleraic diarrhea, chronic diarrhea in giardiasis,antibiotic-associated chronic diarrhea, diarrhea-predominant irritablebowel syndrome, chronic diarrhea associated with maldigestion andmalabsorption, chronic diarrhea in idiopathic primary gastrointestinalmotility disorders, chronic diarrhea associated with collagenouscolitis, surgery-associated acute diarrhea, antibiotic-associated acutediarrhea, infection-associated acute infectious diarrhea, and the like.

The instant invention further provides a method and composition fortreating diarrhea in a subject, said method comprising administering tosaid subject a composition comprising an active lipid in an amountsufficient to prolong the residence time of the lumenal contents of thesmall intestine. The inventive composition can be delivered as a singleunit, multiple unit (for more prolonged effect via enterically coated orsustained release forms) or in a liquid form.

Since cholesterol and triglycerides are so insoluble in plasma, aftermucosal absorption of lipids, the transport of these lipids from theintestine to the liver occurs through lipoproteins called chylomicrons.

While fat absorption from the lumen is rate-limiting for the proximalhalf of the small intestine, chylomicron synthesis or release israte-limiting for the distal one half of the small intestine. As aresult, chylomicrons formed by the distal small intestine are largerthan those from the proximal small intestine (Wu, 1975). In thecapillary bed of the peripheral circulatory system, the enzymelipoprotein lipase hydrolyzes and removes most of the triglycerides fromthe chylomicron. The lipoprotein that remains, now rich in cholesterolesters and potentially atherogenic, is called a chylomicron remnant.This postprandial lipoprotein is then removed from the circulation bythe liver (Zilversmit, Circulation 60(3):473 [1979]).

Elevated levels of atherogenic serum lipids have been directlycorrelated with atherosclerosis (Keinke et al., Q. J. Exp. Physiol.69:781-795 [1984]).

The present invention provides a novel method to minimize atherogenicpostprandial lipemia by optimizing proximal fat absorption. In otherwords, the present invention provides a novel method by whichatherogenic serum lipids can be controlled preabsorptively by the fedmotility response of the small intestine to lumenal fat.

Preabsorptive control depends on the triggering of a specific pattern ofproximal intestinal motility which slows transit to minimize the spreadof fat into the distal gut. After a small meal ofcholesterol-containing, fatty foods, the small intestine limits the siteof fat absorption to the proximal small intestine by generatingnonpropagated motility to slow intestinal transit. Since chylomicronsproduced by the proximal small intestine are small in size, the sizedistribution of postprandial lipoproteins is shifted to minimizepostprandial lipemia. However, during gorging of a high cholesterol,high fat meal, the ability of the small intestine to optimize proximalfat absorption is reduced by the time-dependent fading of the effect offat on nonpropagated motility. As a result, after the first 1-2 hours,faster intestinal transit works to displace lumenal fat into the distalsmall intestine where large, cholesterol-enriched, atherogenicchylomicrons are formed and released into the circulation.

In addition to the dietary effects on intestinal transit, studiessuggest that nicotine inhibits intestinal motility. (McGill [1979];Maida [1990]) (Booyse [1981]) (Carlson [1970]). In the postprandialsituation, this nicotine-related inhibitory effect alters thepotentially protective, braking or nonpropagated pattern of motility. Asa result, nicotine can facilitate the spreading of ingested lipids intothe distal small intestine and impair the preabsorptive control oflipids. The methods of the present invention provide means to minimizethe nicotine-induced inhibition of this postprandial response and tomaximize proximal fat absorption.

Oral pharmaceutical preparations account for more than 80% of all drugsprescribed. It is essential, therefore, to control the multiple factorsthat influence their intestinal absorption as a determinant of ultimatetherapeutic effectiveness.

Disintegration and dissolution are factors determining drug absorptionthat takes place only after a drug is in solution. Drugs ingested insolid form must first dissolve in the gastrointestinal fluid before theycan be absorbed, and tablets must disintegrate before they can dissolve.The dissolution of a drug in the gastrointestinal tract is often therate-limiting step governing its bioavailability. In any given drug,there can be a 2- to 5-fold difference in the rate or extent ofgastrointestinal absorption, depending on the dosage or its formulation.

The rate of gastric emptying bears directly on the absorption ofingested drugs and on their bioavailability. Some drugs are metabolizedor degraded in the stomach, and delayed gastric emptying reduces theamount of active drug available for absorption.

The pharmaceutical industry has developed all sorts of slow and/orsustained-release technology. These efforts have been directed todelaying gastric emptying. Sustained-release formulations employ severalmethods. The most common is a tablet containing an insoluble core; adrug applied to the outside layer is released soon after the medicationis ingested, but drug trapped inside the core is released more slowly.Capsules containing multiparticulate units of drug with coatings thatdissolve at different rates are designed to give a sustained-releaseeffect. However, the basic problem with sustained-release medications isthe considerable variability in their absorption due to the inability tomonitor the individual's ingestion of the medication and thus, inabilityto control transit. Accordingly, slow release of drug in the absence ofslow transit in the gut is meaningless.

The instant invention solves the bioavailability problem in thisinstance. The methods and compositions of this invention enable one tomanipulate the balance of dissolution and gastrointestinal transit byincreasing gastrointestinal residence time.

To facilitate drug absorption in the proximal small intestine, thepresent invention provides a method for prolonging the gastrointestinalresidence time which will allow drugs in any dosage form to morecompletely dissolve and be absorbed. Since the inventive compositionsslow gastrointestinal transit (delays both gastric emptying and smallintestinal transit) a more rapid dissolving dosage form is preferred.

Accordingly, the present invention provides pharmaceutical oral articlesand enteral formulas that slow gastrointestinal transit and prolongresidence time of a substance. The composition of the invention enhancedissolution, absorption, and hence bioavailability of drugs ingestedconcurrently therewith or subsequent thereto.

Pharmaceutical compositions of the present invention can be used in theform of a solid, a solution, an emulsion, a dispersion, a micelle, aliposome, and the like, wherein the resulting composition contains oneor more of the compounds of the present invention, as an activeingredient, in admixture with an organic or inorganic carrier orexcipient suitable for enteral or parenteral applications. The activeingredient can be compounded, for example, with the usual non-toxic,pharmaceutically acceptable carriers for tablets, pellets, capsules,solutions, emulsions, suspensions, and any other form suitable for use.The carriers which can be used include glucose, lactose, gum acacia,gelatin, mannitol, starch paste, magnesium trisilicate, talc, cornstarch, keratin, colloidal silica, potato starch, urea, medium chainlength triglycerides, dextrans, and other carriers suitable for use inmanufacturing preparations, in solid, semisolid, or liquid form. Inaddition auxiliary, stabilizing, thickening and coloring agents andperfumes can be used.

The active lipid is included in the pharmaceutical composition in anamount sufficient to produce the desired effect upon the process orcondition of diseases.

Pharmaceutically acceptable compositions containing the active agent canbe in a form suitable for oral use, for example, as tablets, troches,lozenges, aqueous or oily suspensions, dispersible powders or granules,emulsions, hard or soft capsules, syrups, elixirs or enteral formulas.Compositions intended for oral use can be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions can contain one or more other agentsselected from the group consisting of a sweetening agent such assucrose, lactose, or saccharin, flavoring agents such as peppermint, oilof wintergreen or cherry, coloring agents and preserving agents in orderto provide pharmaceutically elegant and palatable preparations. Tabletscontaining the active ingredient in admixture with non-toxicpharmaceutically acceptable excipients can also be manufactured by knownmethods. The excipients used can be, for example, (1) inert diluentssuch as calcium carbonate, lactose, calcium phosphate or sodiumphosphate; (2) granulating and disintegrating agents such as cornstarch, potato starch or alginic acid; (3) binding agents such as gumtragacanth, corn starch, gelatin or acacia, and (4) lubricating agentssuch as magnesium stearate, stearic acid or talc. The tablets can beuncoated or they can be coated by known techniques to delaydisintegration and absorption in the gastrointestinal tract and therebyprovide a sustained action over a longer period. For example, a timedelay material such as glyceryl monostearate or glyceryl distearate canbe employed. They can also be coated by the techniques described in theU.S. Pat. Nos. 4,256,108; 4,160,452; and 4,265,874, to form osmotictherapeutic tablets for controlled release. Other techniques forcontrolled release, compositions, such as those described in the U.S.Pat. Nos. 4,193,985; and 4,690,822; 4,572,833 can be used in theformulation of the inventive pharmaceutically acceptable compositions.

In some cases, formulations for oral use can be in the form of hardgelatin capsules wherein the active ingredient is mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin. They can also be in the form of soft gelatin capsules whereinthe active ingredient is mixed with water or an oil medium, for example,peanut oil, liquid paraffin, or olive oil.

The methods and compositions of the invention are most needed for drugsthat have slow dissolution characteristics. Since the drug is releasedslowly in such formulations that are now enterically coated or packagedin a sustained release form, there is great potential for the drug to bepassed into the colon still incompletely absorbed. In embodiment of themethod of manipulating the rate of upper gastrointestinal transit, therole of the inventive pharmaceutically acceptable compositions is toincrease the gastrointestinal residence time to allow the poorlydissoluting drugs to be fully absorbed.

In one embodiment of the present invention, the pharmaceuticallyacceptable composition is an enterically coated or a sustained releaseform that permits intestinal transit to be slowed for a prolonged periodof time. The drug can also be packaged in an enterically coated orsustained release form so that it can also be released slowly. Thiscombination would probably have the longest biologic activity and befavored if a high initial drug plasma peak is not desirable.

In an alternative embodiment, inventive pharmaceutically acceptablecompositions are formulated for controlled release (enterically coatedor sustained release form) whereas a rapid release formulation iscontemplated for the drug (tablet or capsule with rapid dissolutioncharacteristics or composition in a liquid form). This simpler strategyis used if the inventive pharmaceutically acceptable composition is ableto “hold” the drug in the proximal small intestine for a period longenough for complete absorption of the drug to take place and a highinitial peak of the drug is desirable.

Another embodiment is a rapid release formulation of the inventivepharmaceutically acceptable composition. This form is administeredfollowing slow release of the drug which is enterically coated or asustained release form.

Also contemplated by the instant invention is the combination of a rapidrelease form of the inventive pharmaceutically acceptable compositionand a rapid release of the drug.

Accordingly, the methods and compositions of the instant invention canbe combined with the existing pharmaceutical release technology toprovide control over not only the gastrointestinal transit and residencetime of a drug, but also over the time of release of the active agent.More specifically, the combination of invention methods and compositionswith existing release technology provides control over the multiplefactors that influence intestinal absorption of a drug. The ability tocontrol such factors enables optimization of the bioavailability andultimate therapeutic effectiveness of any drug.

The present invention provides a means to enhance region-to region(e.g., gut-to-CNS or gut-to gut) communications by way of replicating5-HT as a signal (or releasing 5-HT at a distance as a surrogatesignal). Thus, the present invention provides a way to increase 5-HT inlocations in the central nervous by transmitting a neural signal fromthe gut. Gut-to-brain serotonergic signal replication can be used forpreventing or treating anti-anxiety/panic disorders, depression,phobias, bulimia and other eating disorders, obsessive-compulsivedisorders, mood disorders, bipolar disorders, aggression/anger,dysthmia, alcohol and drug dependence, nicotine dependence, psychosis,improving cognition/memory, improving brain blood flow,antinociception/analgesia, and/or suppression of feeding. The inventivetechnology can replace or supplement the use of serotonin reuptakeinhibitors.

In particular, the invention relates to a method of transmitting to andreplicating at a second location in the central nervous system aserotonergic neural signal originating at a first location in theproximal or distal gut of the mammalian subject. The method involvesadministering by an oral or enteral delivery route to the mammaliansubject a pharmaceutically acceptable composition containing an activeagent, which is an active lipid; serotonin, a serotonin agonist, or aserotonin re-uptake inhibitor; peptide YY or a peptide YY functionalanalog; CGRP, or a CGRP functional analog. The composition is formulatedto deliver the active agent to the first location in the proximal ordistal gut. Substantially simultaneously with the active agent, anadrenoceptor antagonist is also delivered orally or enterally to themammal, either in the same composition or by administering orally orenterally a second separate composition containing the adrenoceptorantagonist. Thus, a serotonergic neural signal is produced in the uppergastrointestinal tract; the signal is transmitted via the intrinsiccholinergic afferent neural pathway to the prevertebral ganglion andthence to the central nervous system. The neural signal is ultimatelyreplicated at the second location in the central nervous system, forexample in the hypothalamus, as a serotonergic neural signal.

Similarly, the inventive technology provides a method of transmitting toand replicating at a second location in the upper gastrointestinal tracta serotonergic neural signal originating at a first location in theproximal or distal gut of a mammal. For example, the first location canbe in the proximal gut and the second location can be elsewhere in theproximal gut or in the distal gut. Or conversely, the first location canbe in the distal gut and the second location can be elsewhere in thedistal gut or in the proximal gut.

A preferred embodiment includes administering by an oral or enteraldelivery route to the mammal a pharmaceutically acceptable compositioncontaining an active agent, which is an active lipid; serotonin, aserotonin agonist, or a serotonin re-uptake inhibitor; peptide YY or apeptide YY functional analog; CGRP, or a CGRP functional analog. Thecomposition is formulated to deliver the active agent to the firstlocation in the proximal or distal gut, whereby a serotonergic neuralsignal is produced, and then transmitted via an intrinsic cholinergicafferent neural pathway and the prevertebral ganglion and is replicatedat the second location as a serotonergic neural signal.

Some embodiments of the method of manipulating the rate of uppergastrointestinal transit of a substance involve slowing the rate ofupper gastrointestinal transit, for example after a meal. This aspect ofthe invention is useful in increasing the absorption or bioavailablityof drugs or for increasing nutrient absorption. In response to luminalfat in the proximal or distal gut, a serotonin (5-HT)-mediatedanti-peristaltic slowing response is normally present. Therefore, someembodiments of the method involve increasing 5-HT in the gut wall byadministering to the mammal and delivering to the proximal and/or distalgut, an active lipid, or serotonin, a serotonin agonist, or a serotoninre-uptake inhibitor.

Alternatively, the active agent is PYY, or a PYY functional analog. PYYor the PYY analog activates the PYY-sensitive primary sensory neurons inresponse to fat or 5-HT. Since the predominant neurotransmitter of thePYY-sensitive primary sensory neurons is calcitonin gene-related peptide(CGRP), in another embodiment, CGRP or a CGRP functional analog is theactive agent.

In other embodiments the point of action is an adrenergic efferentneural pathway, which conducts neural signals from one or more of theceliac, superior mesenteric, and inferior mesenteric prevertebralganglia, back to the enteric nervous system. The active agent is anadrenergic receptor (i.e., adrenoceptor) agonist to activate neuralsignal transmission to the efferent limb of the anti-peristaltic reflexresponse to luminal fat.

Since adrenergic efferent neural pathway(s) from the prevertebralganglia to the enteric nervous system stimulate serotonergicinterneurons, which in turn stimulate enteric opioid interneurons, inother embodiments of the method, the active agent is 5-HT, 5-HT receptoragonist, or a 5-HT re-uptake inhibitor to activate or enhance neuralsignal transmission at the level of the serotoneregic interneurons.

Alternatively, the active agent is an opioid receptor agonist toactivate or enhance neural signal transmission via the opioidinterneurons.

Some embodiments of the method of manipulating the rate of uppergastrointestinal transit of a substance involve accelerating the rate ofgastrointestinal transit, for example after a meal. This aspect of theinvention is useful in countering the transit-slowing effects of opioidmedications or for decreasing nutrient absorption in the treatment ofobesity. In response to luminal fat in the proximal or distal gut, aserotonin-mediated anti-peristaltic slowing response is normallyexhibited. But this anti-peristaltic response to the release of 5-HT inthe proximal or distal gut wall is switched to a peristaltic response to5-HT by administering to the mammal and delivering a PYY receptorantagonist to the proximal and/or distal gut. The PYY antagonist blocksor reduces the activation of primary sensory neurons in response to fator 5-HT. In another embodiment, a calcitonin gene-related peptidereceptor antagonist is contained in the pharmaceutical composition, toblock the action of CGRP, the neurotransmitter of the primary sensoryneurons, which are activated by PYY.

In other embodiments the point of action is an adrenergic efferentneural pathway, which conducts neural signals from one or more of theceliac, superior mesenteric, and inferior mesenteric prevertebralganglia, back to the enteric nervous system. The active agent is anadrenergic receptor (i.e., adrenoceptor) antagonist to block neuralsignal transmission to the efferent limb of the anti-peristaltic reflexresponse to luminal fat.

Since adrenergic efferent neural pathway(s) from the prevertebralganglia to the enteric nervous system stimulate serotonergicinterneurons, which in turn stimulate enteric opioid interneurons, inother embodiments of the method, the active agent is a 5-HT receptorantagonist to block or reduce neural signal transmission at the level ofthe serotoneregic interneurons.

Alternatively, the active agent is an opioid receptor antagonist toblock neural signal transmission via the opioid interneurons.

Some embodiments of the method of manipulating post-prandial visceralblood flow involve increasing visceral blood flow, which includesmesenteric, enteric, and gastric blood flow. This aspect of theinvention is useful in increasing the absorption or bioavailablity ofdrugs or for increasing nutrient absorption. Some embodiments involveincreasing 5-HT in the gut wall by administering and delivering to theproximal and/or distal gut, an active lipid, or serotonin, a serotoninagonist, or a serotonin re-uptake inhibitor.

Alternatively, the active agent is PYY, or a PYY functional analog. PYYor the PYY analog activates the PYY-sensitive primary sensory neurons inresponse to fat or 5-HT. Since the predominant neurotransmitter of thePYY-sensitive primary sensory neurons is calcitonin gene-related peptide(CGRP), in another embodiment, CGRP or a CGRP functional analog is theactive agent.

In other embodiments the point of action is an adrenergic efferentneural pathway, which conducts neural signals from one or more of theceliac, superior mesenteric, and inferior mesenteric prevertebralganglia, back to the enteric nervous system. The active agent is anadrenergic receptor (i.e., adrenoceptor) agonist to activate neuralsignal transmission to the efferent limb of the anti-peristaltic reflexresponse to luminal fat.

Since adrenergic efferent neural pathway(s) from the prevertebralganglia to the enteric nervous system stimulate serotonergicinterneurons, which in turn stimulate enteric opioid interneurons, inother embodiments of the method, the active agent is 5-HT, a 5-HTreceptor agonist, or a 5-HT re-uptake inhibitor to activate or enhanceneural signal transmission at the level of the serotoneregicinterneurons.

Alternatively, the active agent is an opioid receptor agonist toactivate or enhance neural signal transmission via the opioidinterneurons.

Some embodiments of the method of manipulating post-prandial visceralblood flow involve decreasing post-prandial visceral blood flow byadministering a PYY receptor antagonist to the proximal and/or distalgut. The PYY antagonist blocks or reduces the activation of primarysensory neurons in response to fat or 5-HT, thereby decreasingpost-prandial visceral blood flow compared to blood flow without theactive agent.

In another embodiment, a calcitonin gene-related peptide receptorantagonist is the active agent, to block the action of CGRP, thepredominant neurotransmitter of the primary sensory neurons, which areactivated by PYY.

In other embodiments the point of action is an adrenergic efferentneural pathway, which conducts neural signals from one or more of theceliac, superior mesenteric, and inferior mesenteric prevertebralganglia, back to the enteric nervous system. The active agent is anadrenergic receptor (i.e., adrenoceptor) antagonist.

Since adrenergic efferent neural pathway(s) from the prevertebralganglia to the enteric nervous system stimulate serotonergicinterneurons, which in turn stimulate enteric opioid interneurons, inother embodiments of the method, the active agent contained in theactive agent is a 5-HT receptor antagonist to block or reduce neuralsignal transmission at the level of the serotoneregic interneurons.

Alternatively, the active agent is an opioid receptor antagonist toblock neural signal transmission via the opioid interneurons.

Some embodiments of the method of manipulating satiety involve inducingsatiety. Fat in the intestinal lumen can induce satiety. In response toluminal fat in the proximal or distal gut satiety is induced. This fatsignal is serotonin (5-HT)-mediated. Therefore, some embodiments of themethod involve increasing 5-HT in the gut wall by administering to themammal and delivering to the proximal and/or distal gut, an activelipid, or serotonin, a serotonin agonist, or a serotonin re-uptakeinhibitor.

Alternatively, the active agent is PYY, or a PYY functional analog. PYYor the PYY analog activates the PYY-sensitive primary sensory neurons inresponse to fat or 5-HT. Since the predominant neurotransmitter of thePYY-sensitive primary sensory neurons is calcitonin gene-related peptide(CGRP), in another embodiment, CGRP or a CGRP functional analog is theactive agent.

In other embodiments the point of action is an adrenergic efferentneural pathway, which conducts neural signals from one or more of theceliac, superior mesenteric, and inferior mesenteric prevertebralganglia, back to the enteric nervous system. The active agent is anadrenergic receptor (i.e., adrenoceptor) agonist to activate neuralsignal transmission to the efferent limb of the response to luminal fat.

Since adrenergic efferent neural pathway(s) from the prevertebralganglia to the enteric nervous system stimulate serotonergicinterneurons, which in turn stimulate enteric opioid interneurons, inother embodiments of the method, the active agent is 5-HT, a 5-HTreceptor agonist, or a 5-HT re-uptake inhibitor to activate or enhanceneural signal transmission at the level of the serotoneregicinterneurons.

Alternatively, the active agent is an opioid receptor agonist toactivate or enhance neural signal transmission via the opioidinterneurons.

In a most preferred embodiment of the method for inducing satiety acombination of active agents is employed. The combination includesactive lipid, 5-HT, a 5-HT agonist, PYY, and/or a PYY functional analogtogether with an adrenoceptor antagonist. The active lipid, 5-HT, 5-HTagonist, PYY, and/or PYY functional analog initiate the satiety signalfrom the enteric nervous system, while the adrenoceptor antagonistblocks the neural signal transmission of signal from prevertebralganglion back to the gut enteric nervous system, so that the signal isgated in the direction of prevertebral ganglion to the central nervoussystem, particularly projecting from the prevertebral ganglion to thehypothalamus of the mammalian subject.

Some embodiments of the method of manipulating satiety involvesuppressing satiety by administering a PYY receptor antagonist to theproximal and/or distal gut. The PYY antagonist blocks or reduces theactivation of primary sensory neurons in response to fat or 5-HT. Inanother embodiment, a calcitonin gene-related peptide receptorantagonist is the active agent, to block the action of CGRP, theneurotransmitter of the primary sensory neurons, which are activated byPYY.

In other embodiments the point of action is an adrenergic efferentneural pathway, which conducts neural signals from one or more of theceliac, superior mesenteric, and inferior mesenteric prevertebralganglia, back to the enteric nervous system. The active agent is anadrenergic receptor (i.e., adrenoceptor) antagonist.

Since adrenergic efferent neural pathway(s) from the prevertebralganglia to the enteric nervous system stimulate serotonergicinterneurons, which in turn stimulate enteric opioid interneurons, inother embodiments of the method, the active agent is a 5-HT receptorantagonist to block or reduce neural signal transmission at the level ofthe serotoneregic interneurons.

Alternatively, the active agent is an opioid receptor antagonist toblock neural signal transmission via the opioid interneurons.

The invention includes a method for treating visceral pain or visceralhyperalgesia, which involves blocking or substantially reducingactivation, i.e., neural signal transmission, of any of a cholinergicintestino-fugal pathway, one or more prevertebral ganglionic pathways, agangalion to central nervous system pathway, the adrenergic efferentneural pathway, the serotonergic interneuron and/or the opioidinterneuron such that activation thereof is substantially reduced by theaction of the active agent. The result is that the sensation ofesophageal, gastric, biliary, intestinal, colonic or rectal painexperienced by the human subject is reduced. Most preferably the pointof neural blockade, for example one or more of the prevertebral ganglia,prevents transmission of neural signals from the enteric nervous systemto the central nervous system.

In a most preferred embodiment of the method, the pharmaceuticallyacceptable composition includes an opioid agonist specific for theopioid receptors of the prevertebral ganglionic cells, preferably anagonist of 5-HT3, 5-HT1P, 5-HT2, and/or 5-HT4, in combination with anopioid receptor antagonist to enhance activation of the enteric nervoussystem-to-prevertebral ganglion opioid neural pathway. While the opioidagonist will be available to the prevertebral ganglion after absorptioninto the systemic circulation from the lumen, the opioid receptorantagonist, preferably naloxone, acts from the intestinal lumen in theproximal and/or distal gut on the opioid receptors of the entericnervous system to inhibit the effect of the opioid agonist in slowingthe rate of gut transit. Since the opioid antagonist is nearlycompletely eliminated by the liver before reaching systemic circulation,the opioid agonist acts systemically on the prevertebral ganglion toblock the transmission of neural signals to the central nervous system,without incurring an opioid-induced slowing effect on gut transit.

In other embodiments of the method, the point of blockade is thePYY-sensitive primary sensory neurons of the intestinal wall. In oneembodiment, the administered pharmaceutical composition contains a PYYantagonist to prevent or reduce activation of primary sensory neurons inresponse to fat or 5-HT. In another embodiment, a calcitoningene-related peptide receptor antagonist is contained in thepharmaceutically acceptable composition, to block the action of CGRP,the neurotransmitter of the primary sensory neurons, which are activatedby PYY.

Detecting neural pathway activation or blockage is not necessary to thepractice of the inventive methods. However, one skilled in the art isaware of methods for measuring outcomes, such as the rate of intestinaltransit, for example, by using the lactulose breath hydrogen test inhumans to detect an effect on the rate of upper gastrointestinal transitafter treatment in accordance with the method of manipulating uppergastrointestinal transit. For example, the effect on fat-induced slowingof transit can be measured when various agonists and/or antagonists areused, e.g., cholinergic antagonists, such as atropine or hexamethonium,to test for cholinergic pathway activation, propranolol to test foradrenergic pathway activation, ondansetron to test for serotonergicpathway activation, naloxone or another opioid receptor antagonist forthe opioid pathways. In this way, after a standard fat meal, theexpected rate of transit would be accelerated with these agents toconfirm that these pathways were activated. Biochemical orimmunochemical assays can also be performed to quantitate variousneurotransmitters, such as 5-HT or PYY, in biological samples from themammalian subject, e.g., collected intestinal juice. By way of example,serotonin in the sample can be assayed after the intestine is exposed tofat. Ways of collecting intestinal juice for such measurement are known,including by direct aspiration via endoscope or fluoroscopically placednasointestinal tube or using capsules on a string that is equipped toallow serotonin to enter the capsule in the manner of a microdialysate.

Behavioral or subjective indicators of outcome related to outcomes ofsatiety manipulation or the experience of visceral pain are also useful.

The following examples are intended to illustrate, but not limit, thepresent invention.

EXAMPLE I Oleate and Oleic Acid Slow Upper Gut Transit and ReduceDiarrhea in Patients with Rapid Upper Gut Transit and Diarrhea

Rapid transit through the upper gut can result in diarrhea, maldigestionand absorption, and weight loss; and pharmacologic treatment withopiates or anticholinergics often is required. It was tested whetherfatty acids could be used to slow upper gut transit and reduce diarrheain patients with rapid transit and diarrhea.

In a preliminary study, five patients with persistent diarrhea for 3 to22 months, (one each due to vagal denervation, ileal resection forCrohn's disease, and vagotomy and antrectomy, and two due to idiopathiccauses) were studied. Each patient demonstrated rapid upper gut transiton routine lactulose breath hydrogen testing (or variations thereofmeasuring labelled carbon dioxide) (Cammack et al. Gut 23:957-961[1982]). This test relies on the metabolism of certain carbohydratematerials (e.g. lactulose) by the microbial flora within the caecum. Bygenerating gas which can be detected in the expired air, it is possibleto make some estimation about the initial arrival of the administeredmaterial within the colon.

Each patient received orally in random order, 0, 1.6 or 3.2 g of sodiumoleate in 25 mL Ensure (Ross), followed by 100 mL water. Thirty minutesafter each dose of oleate, patients received 10 g lactulose orally,followed by 25 mL water. Breath samples were collected in commerciallyavailable breath testing bags (Quintron, Menomonee Falls, Wis.) every10-15 minutes, and the hydrogen content of the samples was measuredusing a breath analyzer (Microlyzer Model 12, Quintron Instruments,Menomonee Falls, Wis.), calibrated against gas samples of known hydrogenconcentration. With a syringe, a 40-mL sample of the expired breath waswithdrawn from the collection bag and analyzed immediately for hydrogenconcentration (ppm). The hydrogen concentration value from each samplewas plotted against time. Upper gut transit time was defined as the timein minutes from ingestion of lactulose (to) until a rise of H₂ of >10ppm. Data were further analyzed using 1-way repeated measures analysisof variance (ANOVA). Results (mean ± SE): Oleate (g) 0 1.6 3.2 Transittime (min) 46 ± 8.6 116 ± 11.1 140 ± 11.5

Upper gut transit was significantly prolonged by oleate in adose-dependent fashion (p<0.005, significant trend). During prolongedingestion of oleate 15-30 minutes prior to meals, all patients reportedreduced diarrhea. The patient with Crohn's disease reported completeresolution of chronic abdominal pain as well as post prandial bloatingand nausea, and gained 22 lbs. In addition, the patient with vagotomyand antrectomy reported resolution of postprandial dumping syndrome(flushing, nausea, light-headedness).

The effect of an active lipid on transit time was determined in 8 normalhuman subjects (1 male and 7 females with a mean age of 35±2.6 years[SE]) and 45 patients (20 males and 25 females with a mean age of49.1±2.5 [SE], age range from 18 to 90 years) with chronic diarrhea(i.e., continuous diarrhea for more than two months) associated with awide variety of diagnoses and conditions (e.g., Crohn's disease;irritable bowel syndrome; short bowel syndrome; Indiana pouch; AIDS;ulcerative colitis; vagotomy; antrectomy; ileostomy; partial andcomplete colectomy; colon cancer; diabetes mellitus type 1; pancreaticinsufficiency; radiation enteropathy; esophagectomy/gastric pull-up;total and subtotal gastrectomy; gastorjejunostomy), made by referringgastroenterologists. The method was the same as described above, exceptoleic acid (Penta Manufacturing, Livingston, N.J.) replaced sodiumoleate in 50 mL of Ensure emulsion. All subjects refrained from takingantibiotics for at least two weeks before each testing date and duringstool measurement periods. Patients were also instructed to refrain fromanti-diarrheal drugs, laxatives, somatostatin analogues oranticholinergics for at least 48 hours before each test. In both thenormal and patient groups, there was a significant slowing of upper guttransit time in response to oleic acid, as summarized below (p<0.001):Transit time (min) (mean ± SE) Oleic Acid (g) 0 1.6 3.2 Normal 105.2 ±12.1  116 ± 11.1  140 ± 11.5 Patients 29.3 ± 2.8 57.2 ± 4.5  83.3 ± 5.2 

Continuing oleic acid treatment at home was offered to “responders”(i.e., patients who experienced a greater than 100% increase in baselinetransit time with 3.2 g oleic acid). Of the 36 responders out of theoriginal 45 patients, 18 provided records of stool volume and frequencyon- and off-treatment for comparison. The inconvenient and unappealingnature of stool collection and measurement were the primary reasonsreported by responders who chose not to participate in stool collection.After completing a set of three preliminary breath hydrogen tests, eachparticipating responder was asked to refrain from taking oleic acid fortwo days in order to measure off-treatment stool output for a 24-hourperiod. Patients were issued a stool pattern record form and a stoolcollection container with graduated volume markings to record thefrequency and volume of bowel movements. After two days without oleicacid, each patient took 3.2 g of oleic acid mixed with 25 mL of Ensureemulsion three times a day, 30 minutes before breakfast, lunch anddinner. After taking oleic acid for two days, patients recorded stooloutput for another 24-hour period. With this oleic acid emulsiontreatment, stool frequency decreased from 6.9±0.8 to 5.4±0.9 bowelmovements per 24-hour period (p<0.05), and stool volume decreased from1829.0±368.6 to 1322.5±256.9 per 24-hour period (p<0.05). A slight andtransient burning sensation in the mouth or throat was the only adverseeffect reported by any patient taking the oleic acid treatment.

These experiments demonstrate that active lipids, such as oleate andoleic acid, are effective in slowing upper gut transit in adose-dependent manner and reduce diarrhea among patients with rapidtransit and diarrhea. This novel treatment is effective in other chronicdiarrheal conditions associated with rapid transit.

EXAMPLE II Fat in Distal Gut Inhibits Intestinal Transit More PotentlyThan Fat in Proximal Gut

In 4 dogs equipped with duodenal (10 cm from pylorus) and mid-gut (160cm from pylorus) fistulas, intestinal transit was compared across anisolated 150 cm test segment (between fistulas) while 0, 15, 30 or 60 mMoleate was delivered into either the proximal or distal segment of thegut as a solution of mixed micelles in pH 7.0 phosphate buffer at 2mL/min for 90 minutes. The segment of gut not receiving oleate wasperfused with phosphate buffer, pH 7.0, at 2 mL/min. 60 minutes afterthe start of the perfusion, ˜20 μCi of ^(99m)Tc-DTPA(diethylenetriaminepentaacetic acid) was delivered as a bolus into thetest segment. Intestinal transit was then measured by counting theradioactivity of 1 ml samples collected every 5 minutes from thediverted output of the mid-gut fistula.

Intestinal transit was calculated by determining the area under thecurve (AUC) of the cumulative percent recovery of the radioactivemarker. The square root values of the AUC (Sqrt AUC), where 0=norecovery by 30 minutes and 47.4=theoretical, instantaneous completerecovery by time 0, were compared across region of fat exposure andoleate dose using 2-way repeated measures ANOVA. Oleate dose (mM) (mean± SE) Region of fat exposure 15 30 60 Proximal ½ of gut 41.6 ± 1.4 40.6± 10.2 34.4 ± 3.0 Distal ½ of gut 25.6 ± 1.4 18.9 ± 1.5   7.0 ± 3.8Control: buffer into both proximal and distal ½ of gut = 41.4 ± 4.6.

These experiments demonstrate that intestinal transit is slower when fatis exposed in the distal ½ of gut (region effect p<0.01). Theseexperiments also demonstrate that oleate is effective to inhibitintestinal transit in a dose-dependent fashion (dose effect, p<0.05);and that dose dependent inhibition of intestinal transit by oleatedepends on the region of exposure (interaction between region and dose,p<0.01).

EXAMPLE III Case Studies Showing Successful Treatment of Diarrhea withOleic Acid

Postgastrectomy Dumping Syndrome. The patient was a 57 year old femalewith a history of subtotal gastrectomy and gastrojejunostomy for pepticulcer and gastric cancer. Symptoms on presentation of nausea, crampingpain, lightheadedness, bloating and explosive diarrhea occurring afterevery meal were consistent with severe dumping syndrome. These symptomspersisted despite aggressive medical therapy including the use oftincture of opium and anticholinergics. Her upper gut transit times were(min) 16 (0 g oleic acid), 99 (1.6 g oleic acid) and 108 (3.2 g oleicacid). After one pre-meal treatment with oleic acid (3.2 g mixed with 25mL of Ensure), this patient reported immediate benefit. With continuedtreatment with oleic acid (3.2 g mixed with 25 mL of Ensure, gravy orother comestible emulsion three times a day, 30 minutes beforebreakfast, lunch and dinner), she had only rare episodes of dumpingsymptoms (only about once per month). Her weight increased from 118 to130 lbs, and bowel movements decreased from 4 to 5 liquid to 2 to 3formed bowel movements per day.

Diarrhea-Predominant Irritable Bowel Syndrome. The patient was a 39-yearold male with a history of adolescent-onset, persistent diarrhea. Aftera routine gastrointestinal work-up failed to provide an explanation forhis symptoms, he was given the diagnosis of diarrhea-predominantirritable bowel syndrome. He presented with complaints of excessive gas,postprandial bloating, diarrhea and urgency, and 3 to 7 liquid bowelmovements per day. His upper gut transit times were (min) 30 (0 g oleicacid), 117 (1.6 g oleic acid) and 101 (3.2 g oleic acid). Withcontinuing oleic acid treatment as described above, he reported hisbowel frequency reduced to a single, solid bowel movement per day. Healso reported complete relief from the symptoms of gaseousness, bloatingand rectal urgency.

History of Ileal Resection. The patient was a 64 year old female who hadchronic diarrhea since 1990, when she underwent an intestinal resectivesurgery to create an Indiana Pouch from her ileum to drain her rightkidney. After the surgery, the patient had approximately 4 to 6 waterybowel movements per day with a 24-hour stool volume of 950 mL. At thetime of presentation, she had reported a weight loss of 20 lbs over theprevious 6-month period despite greater than normal appetite and foodintake. Her upper gut transit times were (min) 60 (0 g oleic acid), 68(1.6 g oleic acid) and 148 (3.2 g oleic acid). With continuing oleicacid treatment as described above, her 24-hour stool volume decreased to200 mL, and her stool frequency was reduced to a single solid bowelmovement daily.

Short Bowel Syndrome. The patient was a 38-year old male with athirty-year history of Crohn's disease. Five intestinal resections hadresulted in a remainder of about 100 cm of small intestine anddescending colon. He presented at 93 lbs; with severe difficulties withoral intake, and was readied with placement of a central line forlife-long total parenteral nutrition (TPN). He was experiencing morethan 20 bowel movements per day, with pain, bloating and nausea at eachmeal. Baseline upper gut transit time was 14 min. His transit time wasprolonged to 47 and 158 min with 1.6 and 3.2 grams of oleic acid,respectively. After the patient began taking oleic acid three times aday, his stool volume decreased during the first 24-hour period from3400 mL to 1400 mL. Over the course of 2 months of oleic acid treatment,he gained 30 lbs without TPN, and he was able to enjoy an unrestricteddiet without symptoms.

A 42-year-old female patient with a history of Crohn's disease andintestinal resective surgeries developed severe diarrhea after herlatest intestinal resection and iliostomy. Before treatment, her stoolvolume was about 1025 mL per day. With oleic acid (6.6 grams in 50 mL ofEnsure), her stool volume decreased to 600 mL per day.

EXAMPLE IV Administration of Active Lipid Increases Drug Bioavailability

Relatively rapid basal upper gut transit in Patients with InflammatoryBowel Disease (IBD). The mean upper gut transit time for IBD patients(n=18) at 0 grams of oleic acid was 79.1±11.0 min., compared to118.7±9.8 min for normal subjects (n=5)(p=0.04, t-test).

Measurement of basal drug bioavailability. The hypothesis that thebioavailability of oral drug is lower in IBD patients was tested bymeasuring serum levels of acetaminophen after oral administration of1000 mg of this drug in a liquid formulation. Acetaminophen was chosen,because it is absorbed rapidly and almost exclusively and entirely inthe proximal intestine; it is safe in a therapeutic dose range; and isonly minimally bound to plasma proteins. After subjects ingested thedrug, periodic samples of blood were collected from a plastic tubeinserted into a vein in each subject's arm. The blood was then analyzedspectrophotometrically for concentration of acetaminophen. Peak plasmalevel, time to peak concentration and area under the curve (AUC;representing the plasma acetaminophen concentration over time) werederived from these data. Relative drug bioavailability was determined bycomparing AUC values. In control experiments without oleic acid, IBDpatients had a smaller AUC than normal subjects, consistent with loweracetaminophen bioavailability; the mean AUC for normal patients (n=5)was 1438.9±208.5. The mean AUC for IBD patients (n=18) was 687.3±98.2.(p<0.05, t-test).

Active lipid increases upper gut transit time and drug bioavailability.The mean transit time for normal subjects (n=5) at 0 grams of oleic acidwas 118.7±9.8 min, at 4 grams of Oleic acid was 136.0±15.4 min. (P<0.05,t-test). The mean AUC for normal subjects at 0 grams of oleic acid was1438.9±208.5; at 4 grams of oleic acid it was 1873.3±330.5 (p<0.05,t-test). The mean transit time for IBD patients (n=18) at 0 grams ofoleic acid was 79.1±11.0 min; at 4 grams of oleic acid it was 114.6±16.0min. (p<0.05, t-test). The mean AUC for IBD patients at 0 grams of oleicacid was 687.3±98.2; at 4 grams of oleic acid it was 1244.9±250.4.(p<0.05, t-test). These data show that oleic acid slowed gut transittime and increased bioavailability of the drug in both normal and IBDgroups.

EXAMPLE V Manipulation of the Rate of Upper Gastrointestinal Transit

The experiments described below are based on a previously describedchronic multi-fistulated dog model, employing surgically fistulated maleor female mongrel dogs weighing about 25 kg each. (Lin, H. C. et al.,Inhibition of gastric emptying by glucose depends on length of intestineexposed to nutrient, Am. J. Physiol. 256:G404-G411 [1989]). The smallintestines of the dogs were each about 300 cm long from the pylorus tothe ileal-cecal valve. The duodenal fistula was situated 15 cm from thepylorus; the mid-gut fistula was situated 160 cm from the pylorus.Occluding Foley catheters (balloon catheters that are inflated toproduce a water-tight seal with the luminal surface) were placed intothe distal limb of a duodenal fistula and a mid-gut fistula, fat orother test agents were administered luminally to the thuscompartmentalized “proximal” section of the gut, i.e., between thefistulas, or to the compartmentalized “distal” section of the gut, i.e.,beyond the mid-gut fistula. Perfusate was pumped into a test sectionthrough the catheter at a rate of 2 mL/minute. Test agents wereadministered along with buffer perfusate, but some test agents wereadministered intravenously, where specifically noted.

Intestinal transit measurements were made by tracking the movement of aliquid marker across the approximately 150 cm intestinal test segment bydelivering about 20 μCi ^(99m)Tc chelated to diethyltriamine pentaaceticacid (DTPA) (Cunningham, K. M. et al., Use of technicium-99m(V)thiocyanate to measure gastric emptying of fat, J. Nucl. Med.32:878-881 [1991]) as a bolus into the test segment after 60 minutes ofa 90-minute perfusion. The output from the mid-gut fistula was collectedevery 5 min thereafter for 30 minutes, which period is illustrated inFIGS. 1-13. Using a matched dose of ^(99m)Tc to represent the originalradioactivity (Johansson, C., Studies of gastrointestinal interactions,Scand. J. Gastroenterol. 9(Suppl 28):1-60 [1974]; Zierler, K., Asimplified explanation of the theory of indicator dilution formeasurement of fluid flow and volume and other distributive phenomena,Bull. John Hopkins 103:199-217 [1958]), the radioactivity delivered intothe animal as well as the radioactivity of the recovered fistula outputwere all measured using a gamma well counter. After correcting allcounts to time zero, intestinal transit was calculated as the cumulativepercent recovery of the delivered ^(99m)Tc-DTPA. This method has beenwell validated over the years and appreciated for its advantage ofminimal inadvertent marker loss. To demonstrate this point, we perfusedphosphate buffer, pH 7.0, through the proximal gut and followed thecumulative recovery of this marker (% recovery) over time (n=1). Therewas a very high level of marker recovery, with 90% of the markerrecovered by 30 minutes and 98% of the marker recovered by 45 minutes.

(1) Slowing of intestinal transit by PYY depends onondansetron-sensitive 5-HT-mediated pathway. Peptide YY (PYY) slowstransit and is a signal for luminal fat (Lin, H. C. et al., Fat-inducedileal brake in the dog depends on peptide YY, Gastroenterol.110(5):1491-95 [1996b]; Lin, H. C. et al., Slowing of intestinal transitby fat in proximal gut depends on peptide YY, Neurogastroenterol.Motility 10:82 [1998]). Since serotonin (5-HT) can also be a signal forfat (Brown, N. J. et al., The effect of a 5HT3 antagonist on the ilealbrake mechanism in the rat, J. Pharmacol. 43:517-19 [1991]; Brown, N. J.et al. [1993]), the hypothesis was tested that the slowing of transit byPYY can depend on a 5-HT-mediated pathway by comparing the rate ofmarker transit during the administration of PYY in the presence orabsence of ondansetron (Ond; a 5-HT receptor antagonist) in the proximalversus distal gut (n=2 for each treatment).

Normal saline (0.15 M NaCl) or PYY (0.8 μg/kg/h) was administeredintravenously over a 90 minute period, while phosphate buffer, pH 7.0,was perfused into the lumen of the proximal gut through the duodenalfistula at a rate of 2 mL/min for the 90 minutes and was recovered fromthe output of the mid-gut fistula. The results are summarized in FIG. 1.Transit was slowed by intravenous PYY, with recovery of the markerdecreased from 75.1±3.6% (control: IV normal saline [NS]+luminal normalsaline, i.e., NS-NS in FIG. 1) to 17.1±11.0% (IV PYY+luminal normalsaline, i.e., PYY-NS in FIG. 1). This effect was abolished by adding thespecific 5-HT receptor antagonist ondansetron (0.7 mg/kg/h) to thebuffer introduced into the proximal gut so that recovery increased to78.3±4.8% (IV PYY+luminal Ond proximal, i.e., PYY−Ond in prox in FIG. 1)but not by ondansetron in the distal gut, which decreased recovery to12.9±12.9% (IV PYY+Ond in Distal, i.e., PYY−Ond in Dist). These resultsimply that slowing of transit by PYY depended on a 5-HT-mediated pathwaylocated in the segment of the small intestine where transit wasmeasured.

(2) The fat induced jejunal brake depends on an ondansetron-sensitiveserotonin (5-HT)-mediated pathway. The hypothesis was tested thatslowing of transit by fat depends on a serotonergic pathway by comparingintestinal transit during perfusion with buffer or oleate in thepresence or absence of the ondansetron, a 5-HT receptor antagonist, inthe proximal gut (n=3 each treatment). Buffer or 60 mM oleate wasperfused through the duodenal fistula into the lumen of the proximal gutfor a 90-minute period, in the manner described in Example V.(1), alongwith a bolus of normal saline+ondansetron (0.7 mg/kg) at the start oftransit measurement. The rate of intestinal transit was slowed by thepresence of oleate (p<0.05) in an ondansetron-sensitive manner.(p<0.05). The results are summarized in FIG. 2.

Specifically, ondansetron increased recovery of marker in the perfusatefrom 41.6±4.6% (mean±SE) (luminal oleate+luminal normal saline, i.e.,Oleate-NS in FIG. 2) to 73.7±10.6% (luminal oleate+luminal ondansetron,i.e., Oleate-Ond in FIG. 2) during oleate perfusion but decreasedrecovery from 96.0±4.0% (luminal phosphate buffer+luminal normal saline,i.e., Buffer-NS in FIG. 2) to 57.9±15.9% (luminal buffer+luminalondansetron, i.e., Buffer-Ond in FIG. 2) during buffer perfusion. Theseresults imply that slowing of intestinal transit by the fat-inducedjejunal brake and the acceleration of intestinal transit by bufferdistension both depended on an ondansetron-sensitve 5-HT-mediatedpathway.

(3) The fat-induced ileal brake depends on an ondansetron-sensitive,efferent serotonin (5-HT)-mediated pathway. The fistulated dog modelallows for the ileal brake (oleate in distal gut, buffer in proximalgut) to be separated into the afferent (distal) vs. efferent (proximal)limb of the response. By delivering ondansetron luminally into eitherthe proximal or distal gut, intestinal transit was slowed by the ilealbrake (66.4±1.5% [Control in FIG. 3] vs. 26.2±18.0% [Ileal Brake in FIG.3]; p<0.05). But the ileal brake was abolished by ondansetron deliveredto the proximal gut (62.5±10.1%; Ond in Prox in FIG. 3; n=4) but notdistal gut (17.4±8.8%; Ond in Dist in FIG. 3; n=4). These results implythat the slowing of intestinal transit by fat in the distal gut dependson an efferent, 5-HT-mediated pathway. Since ondansetron abolished thejejunal brake in Example V.(1) when delivered with fat and abolished theileal brake in Example V.(2) when delivered with buffer, thisregion-specific result cannot be explained by inactivation of drug byfat, differences in permeability or absorption.

(4) Ondansetron abolishes the fat-induced ileal brake in adose-dependent manner. The fat-induced ileal brake was abolished by the5-HT receptor antagonist ondansetron in a dose-dependent manner.Perfusion of buffer was through both the duodenal and mid-gut fistulas(2 mL/min over 90 minutes); the buffer administered to the mid-gutfistula contained normal saline (Buffer Control in FIG. 4) or 60 mMoleate to induce the ileal brake response (Ileal Brake in FIG. 4).During the ileal brake response, ondansetron was added at to as a singlebolus in the following doses (mg): 6.25; 12.5; and 25. Results are shownin FIG. 4.

Oleate induced the ileal brake (24.1% marker recovery [Ileal brake inFIG. 4] vs. 81.2% marker recovery for the Buffer Control). The ilealbrake was abolished by ondansetron delivered into the proximal gut in adose-dependent manner (35.4% marker recovery at 6.25 mg ondansetron,55.8% marker recovery at 12.5 mg ondansetron, and 77.6% marker recoveryat 25 mg ondansetron).

(5) Fat in the distal gut causes the release of 5-HT from the proximalgut. To test the hypothesis that fat in the distal gut causes therelease of 5-HT in the proximal gut, the amount of 5-HT collected fromthe output of the mid-gut fistula (proximal gut 5-HT) over a 90-minuteperiod of buffer perfusion through both the duodenal and mid-gutfistulas (2 mL/min); buffer (control) or oleate (60 mM) was administeredto the distal gut (n=1). The amount of 5-HT was determined using anELISA kit specific for 5-HT (Sigma; Graham-Smith, D. G., The carcinoidsyndrome, In: Topics in Gastroenterology, Truclove, S. C. and Lee, E.(eds.), Blackwells, London, p. 275 [1977]; Singh, S. M. et al.,Concentrations of serotonin in plasma—a test for appendicitis?, Clin.Chem. 34:2572-2574 [1988]). The amount of 5-HT released by the proximalgut increased in response to fat in the distal gut from 100 μg in thecontrol (buffer minus oleate) to 338 μg (buffer plus oleate to distalgut), showing that 5-HT is released in the proximal gut in response tofat in the distal gut. Thus, the release of 5-HT by the proximal gut canserve as a relayed signal for fat in the distal gut. The relayed releaseof 5-HT in the proximal gut in response to fat in the distal gut isconsistent with Example V.(2), showing that slowing of intestinaltransit by fat depends on an efferent 5-HT-mediated pathway to theproximal gut.

(6) Ondansetron abolishes the fat-induced ileal brake when administeredluminally but not intravenously. To test the hypothesis that the effectof ondansetron is peripheral rather than systemic, ondansetron (0.7mg/kg/h) was either delivered through the duodenal fistula into theproximal gut (luminal ondansetron, i.e., Ond in prox in FIG. 5) oradministered intravenously (i.e., iv Ond in FIG. 5) during fat-inducedileal brake (60 mM oleate input through the mid-gut fistula into thedistal gut as described above, n=1). Compared to ileal brake (29% markerrecovered), the marker recovery increased to 78% with luminalondansetron, but intravenous ondansetron had no effect (43% markerrecovery). This implies that the 5-HT receptor antagonist workedperipherally (gut) rather than systemically.

(7) The slowing of intestinal transit by distal gut 5-HT depends on anondansetron-sensitive 5-HT-mediated pathway in the proximal gut(efferent) and distal gut (afferent). To test the hypothesis thatintestinal transit is slowed by 5-HT in the distal gut via a5-HT-mediated pathway(s), intestinal transit with 5-HT (0.05 mg/kg/h)administered to the distal gut was measured to compare the effect ofondansetron (0.7 mg/kg) administered in a bolus either in the proximalgut or distal gut (n=2 each treatment). The results are summarized inFIG. 6. Marker recovery decreased from 75.1±2.5% (Buffer Control in FIG.6) to 35.8±2.1% (buffer+5-HT in the distal gut, minus ondansetron, i.e.,5-HT in Dist in FIG. 6) but this slowing effect was abolished byondansetron administered to either the proximal gut (70.6±3.5% recovery;Ond in Prox in FIG. 6) or distal gut (76.9±4.2% recovery; Ond in Dist inFIG. 6). These results imply that distal gut 5-HT slows intestinaltransit via 5-HT3 receptor-dependent pathways in both afferent (distal)and efferent (proximal) limb of the response. (See also, Brown, N. J. etal., Granisetron and ondansetron: effects on the ileal brake mechanismin the rat, J. Pharm. Pharmacol. 45(6):521-24 [1993]). This resultcontrasts with that for fat in the distal gut (see, Example V.[3]) toimply that the afferent limb of the response to fat involves a signalother than 5-HT, such as PYY.

(8) 5-HT in the distal gut slows intestinal transit in a dose-dependentmanner. Intestinal transit during buffer perfusion of both the proximaland distal guts (81.2% recovery) was slowed by 5-HT in distal gut sothat marker recovery decreased to 73.8% at 2 mg 5-HT (0.033 mg5-HT/kg/h), 53.1% at 3 mg (0.05 mg 5-HT/kg/h) and 11.6% at 4 mg (0.066mg 5-HT/kg/h) dose over a 90 minute period (n=1).

(9) 5-HT in the distal gut causes release of 5-HT in the proximal gut.To test the hypothesis that 5-HT in the distal gut causes the release of5-HT in the proximal gut, the amount of 5-HT collected from the outputat the mid-gut fistula (Proximal gut 5-HT) over a 90-minute period ofbuffer perfusion through both the duodenal and mid-gut fistulas (2mL/min each) was compared in the presence or absence of 5-HT (0.05mg/kg/h) administered to the distal gut (n=1). 5-HT concentration wasdetermined using an ELISA kit specific for 5-HT (Sigma). The amount of5-HT released by the proximal gut increased from 156 μg in the control(minus distal 5-HT) to 450 μg (plus 5-HT to distal gut), implying that5-HT is released by the proximal gut in response to 5-HT in the distalgut. Thus, the release of 5-HT by the proximal gut can serve as arelayed signal for distal gut 5-HT. This relayed release of 5-HT in theproximal gut explains the results of Example V.(6) showing that theslowing of intestinal transit by distal gut 5-HT was abolished byondansetron in the proximal gut (efferent limb of response) as well asin the distal gut (afferent limb of response).

(10) Intravenous PYY causes release of 5-HT in the proximal gut. Theamount of 5-HT released from the proximal gut in response to intravenousPYY or saline (Control) during buffer perfusion (2 mL/min over 90minutes) through both the duodenal and mid-gut fistulas was measured totest the hypothesis that intravenous PYY (0.8 mg/kg/h) causes therelease of 5-HT in the proximal gut. 5-HT was measured as in ExampleV.(9) above. The amount of 5-HT released by the proximal gut increasedfrom 140.1 μg (Control) to 463.1 μg in response to intravenous PYY.

This result was comparable with the response when 60 mM oleate wasadministered to the distal gut (buffer only to the proximal gut) duringthe perfusion without intravenous PYY (509.8 μg of 5-HT; n=1), whichimplies that the release of 5-HT in the proximal gut stimulated by fatin the distal gut can be mediated by PYY.

(11) Slowing of intestinal transit by fat in the distal gut depends onan extrinsic adrenergic neural pathway. A distension-inducedintestino-intestinal inhibitory neural reflex projects through theceliac prevertebral celiac ganglion via a cholinergic afferent and anadrenergic efferent (Szurszewski, J. H. and King, B. H., Physiology ofprevertebral ganglia in mammals with special reference to interiormesenteric ganglion, In: Handbook of Physiology: The GastrointestinalSystem, Schultz, S. G. et al. (eds.), American Physiological Society,distributed by Oxford University Press, pp. 519-592 [1989]). Intestinaltransit was measured during fat perfusion of the distal small intestinein the presence or absence of intravenous propranolol (50 μg/kg/h; n=2),a β-adrenoceptor antagonist, to test the hypothesis that the slowing ofintestinal transit by fat in the distal gut also depends on anadrenergic pathway. Perfusion of buffer was through both the duodenaland mid-gut fistulas (2 mL/min over 90 minutes); the buffer administeredto the mid-gut fistula contained 60 mM oleate. The results areillustrated in FIG. 7.

Intestinal transit was slowed by distal gut fat (79.7±5.8% markerrecovery [Buffer Control in FIG. 7] compared to 25.8±5.2% recovery withfat perfusion into the distal gut [Oleate-NS in FIG. 7]). Intravenouspropranolol abolished this jejunal brake effect so that recoveryincreased to 72.1±4.7% (oleate+propanolol, i.e., Oleate-Prop in FIG. 7),implying that the slowing of transit by fat in the distal gut depends ona propranolol-sensitive, adrenergic pathway. This result supports thehypothesis that the response to fat involves an adrenergic efferent,such as the extrinsic nerves projecting through the prevertebralganglia.

(12) Slowing of intestinal transit by PYY depends on an extrinsicadrenergic neural pathway. Intestinal transit during buffer perfusion ofthe proximal and distal small intestine in the presence or absence ofintravenous propranolol (50 μg/kg/h; n=2) was measured, to test thehypothesis that the slowing of intestinal transit by PYY (a fat signal)also depends on an adrenergic pathway. Perfusion was through bothfistulas as described in Example V.(11) except that oleate was notadministered to the distal gut, and, instead, 30 μg PYY (0.8 mg/kg/h)was administered intravenously during the 90 minute perfusion period.The results are summarized in FIG. 8.

Slowing of intestinal transit by PYY (78.1±2.2% marker recovery minusPYY [Buffer Control in FIG. 8] vs. 11.8±5.4% recovery with intravenousPYY [PYY-NS in FIG. 8]) was abolished by intravenous propranolol. In thepresence of propanolol, marker recovery increased to 66.3±3.1% (PYY-Propin FIG. 8). This result implies that the slowing of transit by PYYdepends on a propranolol-sensitive, adrenergic pathway, which supportsthe hypothesis that the response to PYY involves an adrenergic efferentsuch as the extrinsic nerves projecting through the prevertebralganglia.

(13) Slowing of intestinal transit by 5-HT in the distal gut depends onan extrinsic adrenergic neural pathway. Intestinal transit during bufferperfusion of the proximal and distal small intestine in the presence orabsence of intravenous propranolol (50 μg/kg/h; n=2) was measured, totest the hypothesis that the slowing of intestinal transit by 5-HT inthe distal gut also depends on an adrenergic pathway. Buffer perfusionwas through both fistulas as described in Example V.(12) except that5-HT (0.05 mg/kg/h) was administered to the distal gut during the 90minute perfusion period. The results are summarized in FIG. 9.

Slowing of intestinal transit by 5-HT (83.3±3.3% marker recovery minus5-HT [Buffer Control in FIG. 9] vs. 36.1±2.3% recovery withadministration of 5-HT to the distal gut [5-HT-NS in FIG. 9]) wasabolished by intravenous propranolol. In the presence of propanolol,marker recovery increased to 77.7±7.6% (5-HT-Prop in FIG. 9). Thisresult implies that the slowing of transit by 5-HT depends on apropranolol-sensitive, extrinsic adrenergic pathway, perhaps similar tothat responsible for the response to distal gut fat.

(14) Intestinal transit is slowed by norepinephrine in a 5-HT-mediatedneural pathway. Intestinal transit during buffer perfusion of theproximal and distal small intestine with intravenous norepinephrine (NE;adrenergic agent) in the presence or absence of the 5-HT receptorantagonist ondansetron was measured, to test the hypothesis that theslowing of intestinal transit also depends on an adrenergic efferentpathway. Perfusion of buffer was through both the duodenal and mid-gutfistulas (2 mL/min over 90 minutes); norepinephrine (0.12 μg/kg/h) wasadministered intravenously during the 90 minute perfusion period; andnormal saline with or without ondansetron (0.7 mg/kg/h; n=2) wasadministered in the perfusate to the proximal gut. The results aresummarized in FIG. 10.

Intestinal transit was slowed by NE so that marker recovery was reducedfrom 76.9% (Buffer Control in FIG. 10) to 13.3% (NE-NS in FIG. 10).Ondansetron abolished this slowing effect with marker recovery increasedto 63.4% (NE-Ond in FIG. 10), to implies that NE (adrenergic efferent)slows transit via a 5-HT-mediated pathway. This result confirms thatslowing of intestinal transit is mediated by an adrenergic efferentprojecting from the prevertebral ganglion to the gut action on a5-HT-mediated pathway.

(15) The fat-induced jejunal brake depends on the slowing effect of analoxone-sensitive, opioid neural pathway. To test the hypothesis thatthe slowing of intestinal transit depended on an opioid pathway, theproximal gut was perfused (2 mL/minute for 90 minutes) with buffercontaining 60 mM oleate and 0 (normal saline), 3, 6, or 12 mg ofnaloxone mixed therein, an opioid receptor antagonist. As shown in FIG.11, the fat-induced jejunal brake response depended on the dose ofnaloxone mixed with the oleate (p<0.05, 1-way ANOVA)(n=7). Specifically,marker recovery was 30.0±3.6% with 0 mg naloxone, 41.0±5.2% with 3 mgnaloxone, 62.8±8.2% with 6 mg naloxone and 60.6±6.1% with 12 mgnaloxone. This result demonstrates that proximal gut fat slowsintestinal transit via opioid pathway.

(16) The effect of naloxone was specific for fat-triggered feedback.Intestinal transit was compared during perfusion of the proximal gutwith buffer containing 0 (normal saline) or 6 mg naloxone (n=3). Therate of intestinal transit was not significantly affected by the opioidreceptor antagonist naloxone when fat was not present in the proximalgut. Marker recovery was 88.0±1.3% with naloxone and 81.3±6.1% withoutnaloxone. This implies that the accelerating effect of naloxone wasspecific for reversing the jejunal brake effect of fat.

(17) The fat-induced ileal brake depends on the slowing effect of anefferent, naloxone-sensitive, opioid neural pathway. The fistulated dogmodel allowed for the compartmentalization of the afferent limb (distalgut) from efferent limb (proximal gut) of the fat-induced ileal brake.To test for the location of the opioid pathway involved in the slowingof transit by fat, perfusion of buffer was through both the duodenal andmid-gut fistulas (2 mL/min over 90 minutes); the buffer administeredthrough the mid-gut fistula to the distal gut contained 60 mM oleate toinduce the ileal brake; 6 mg naloxone was delivered into either theproximal or distal gut (n=11). The results are summarized in FIG. 12.

Naloxone delivered to the proximal gut increased marker recovery from34.6±4.8% to 76.2±5.2% (Naloxone in Prox in FIG. 12), but naloxonedelivered to the distal gut had no effect on the ileal brake (markerrecovery of 29.4±5.4% [Naloxone in Dist in FIG. 12]). This resultimplies that the fat-induced ileal brake depends on an efferent,naloxone-sensitive opioid pathway, because an identical amount ofnaloxone was delivered into either of the two compartments, but theaccelerating effect only occurred when naloxone was delivered into theefferent compartment. Therefore, an opioid pathway is involved that islocated peripherally, rather than systemically. The accelerating effectin response to the opioid receptor antagonist is a result of theefferent location of the opioid pathway. It cannot be explained on thebasis of chemical interaction with the perfusate, since the accelerationof transit was seen when naloxone was mixed with oleate in ExampleV.(15), as well as with buffer in this experiment.

(18) Mu and kappa opioid antagonists abolish fat-induced ileal brake.The fat-induced ileal brake (marker recovery 33.1%) was abolished by amu antagonist (H2186, Sigma) delivered into the proximal gut so thatmarker recovery increased to 43.8% at 0.037 mg H2186, 88.2% at 0.05 mgH2186 and 66.8% at 0.1 mg H2186 over 90 minutes. A similar effect wasseen when a kappa antagonist (H3116, Sigma) was used (marker recoveryincreased to 73.2%% at 0.075 mg H3116, 90.9% at 0.1 mg H3116, and 61.8%at 0.125 mg H3116 over 90 minutes; n=1).

(19) Slowing of intestinal transit by distal gut 5-HT depends on analoxone-sensitive, opioid neural pathway. In Example V.(5), 5-HT in thedistal gut slowed intestinal transit, similar to the effect of fat inthe distal gut. Since the ileal brake induced by fat in the distal gutwas shown to depend on an efferent, naloxone-sensitive opioid pathway(Example V.(17), it was tested whether the slowing of intestinal transitin response to 5-HT in the distal gut also depends on an efferent,opioid pathway. Buffer was perfused into both the proximal and distalguts at 2 mL/minute for 90 minutes. Either normal saline (Buffer Controlin FIG. 13) or 5-HT (0.05 mg/kg/h; 5-HT in Dist in FIG. 13) wasadministered to the distal gut over the 90 minute perfusion. When theperfusate to the distal gut contained 5-HT (i.e., 5-HT in Dist),naloxone (6 mg) was simultaneuosly delivered through the duodenalfistula to the proximal gut over the 90 minutes (Naloxone in Prox inFIG. 13). Results are summarized in FIG. 13.

First, intestinal transit was slowed by 5HT in the distal gut. Markerrecovery was reduced from 79.4±4.1% (Buffer Control) to 37.0±1.8% (5-HTin Dist). Second, naloxone in proximal gut abolished this slowing effectwith marker recovery increased to 90.1±4.6% (Naloxone in Prox). Theseresults imply that slowed intestinal transit in response to 5-HT in thedistal gut, depends on an efferent opioid pathway.

Although the invention has been described with reference to thedisclosed embodiments, those skilled in the art will readily appreciatethat the specific embodiments taught hereinabove are only illustrativeof the invention. It should be understood that various modifications canbe made without departing from the spirit of the invention.

1. A method of manipulating the rate of upper gastrointestinal transitof a substance in a mammal having an intrinsic cholinergic afferentneural pathway projecting from a peptide YY-sensitive primary sensoryneuron in the intestinal wall to a prevertebral celiac ganglion andhaving an adrenergic efferent neural pathway projecting from saidganglion to one or more enterochromaffin cells in the intestinal mucosaand/or to a serotonergic interneuron linked in a myenteric plexus and/orsubmucous plexus to an opioid interneuron, said opioid interneuron alsobeing linked by an intestino-fugal opioid pathway projecting to saidganglion, with one or more neural connections to the central nervoussystem and back to the gut projecting from the ganglion, said methodcomprising: providing a pharmaceutically acceptable composition,comprising an active agent selected from the group consisting of (A)peptide YY-functional analogs, and (B) antagonists of receptors for (A);and administering the pharmaceutically acceptable composition to themammal, said active agent being delivered in an amount and underconditions such that the cholinergic intestino-fugal pathway, at leastone prevertebral ganglionic pathway, the adrenergic efferent neuralpathway, the serotonergic interneuron and/or the opioid interneuron areactivated by the action of (A), whereby the rate of uppergastrointestinal transit is slowed, or such that activation of thecholinergic intestino-fugal pathway, at least one prevertebralganglionic pathway, the adrenergic efferent neural pathway, theserotonergic interneuron and/or the opioid interneuron is blocked by theaction of (B), whereby the rate of upper gastrointestinal transit isaccelerated.
 2. The method of claim 1, wherein administering thepharmaceutically acceptable composition to the mammal further comprisesadministering the pharmaceutically acceptable composition by a deliveryroute selected from the group consisting of oral, intravenous,intraperitoneal, and nasal.
 3. A method of manipulating satiety in amammalian subject having a cholinergic afferent neural pathwayprojecting from a peptide YY-sensitive primary sensory neuron in theintestinal wall to a prevertebral celiac ganglion and having anadrenergic efferent neural pathway projecting from said ganglion to oneor more enterochromaffin cells in the intestinal mucosa and/or to aserotonergic interneuron linked in amyenteric plexus to an opioidinterneuron, said opioid interneuron also being linked by anintestino-fugal opioid pathway projecting to said ganglion, with one ormore neural connections to the central nervous system and back to thegut projecting from the ganglion, said method comprising: providing apharmaceutically acceptable composition, comprising an active agentselected from the group consisting of (A) peptide YY functional analogs,and (B) antagonists of receptors for (A); and administering thepharmaceutically acceptable composition to the mammal, said active agentbeing delivered in an amount and under conditions such that thecholinergic intestino-fugal pathway, one or more prevertebral ganglionicpathways, adrenergic efferent neural pathway, the serotonergicinterneuron and/or the opioid interneuron are activated by the action of(A), whereby a state of satiety is induced, or such that activation ofthe cholinergic intestino-fugal pathway, prevertebral ganglionicpathways, ganglion to central nervous system pathways, central nervoussystem pathways, adrenergic efferent neural pathway, the serotonergicinterneuron and/or the opioid interneuron is blocked by the action of(B), whereby satiety is suppressed.
 4. The method of claim 3, wherein aneuronal pathway projecting from said ganglion to the hypothalamus ofthe subject is activated by the action of any of (A) on the primarysensory neuron.
 5. The method of claim 3, wherein administering thepharmaceutically acceptable composition to the mammal further comprisesadministering the pharmaceutically acceptable composition by a deliveryroute selected from the group consisting of oral, intravenous,intraperitoneal, and nasal.
 6. A method of inducing satiety in a mammalhaving an intrinsic cholinergic afferent neural pathway projecting froma peptide YY-sensitive primary sensory neuron in the intestinal wall toa prevertebral celiac ganglion and having a adrenergic efferent neuralpathway projecting from said ganglion to one or more enterochromaffincells in the intestinal mucosa and/or to a serotonergic interneuronlinked in a myenteric plexus and/or submucous plexus to an opioidinterneuron, said opioid interneuron also being linked byanintestino-fugal opioid pathway projecting to said ganglion, with oneor more neural connections to the central nervous system and back to thegut projecting from the ganglion, said method comprising: providing apharmaceutically acceptable composition, comprising peptide YYfunctional analogs; and administering the pharmaceutically acceptablecomposition to the mammal, said peptide YY analogs being delivered in anamount and under conditions such that the cholinergic intestino-fugalpathway, prevertebral ganglionic pathways, ganglion to central nervoussystem pathways, adrenergic efferent neural pathway, the serotonergicinterneuron and/or the opioid interneuron are activated by the action ofsaid peptide YY analogs, whereby a state of satiety is induced in themammal.
 7. The method of claim 6, wherein a neuronal pathway from saidganglion to the hypothalamus of the mammal is activated by the action ofsaid peptide YY analogs on the primary sensory neuron.
 8. The method ofclaim 6, wherein administering the pharmaceutically acceptablecomposition to the mammal further comprises administering thepharmaceutically acceptable composition by a delivery route selectedfrom the group consisting of oral, intravenous, intraperitoneal, andnasal.
 9. A method of treating visceral pain or visceralhypersensitivity in a human subject having a cholinergic afferent neuralpathway projecting from a peptide YY-sensitive primary sensory neuron inthe intestinal wall to a prevertebral celiac ganglion and having aadrenergic efferent neural pathway projecting from said ganglion to oneor more enterochromaffin cells in the intestinal mucosa and/or to aserotonergic interneuron linked in a myenteric plexus to an opioidinterneuron, said opioid interneuron also being linked by anintestino-fugal opioid pathway projecting to said ganglion, with one ormore neural connections to the central nervous system and back to thegut projecting from the ganglion, said method comprising: providing apharmaceutically acceptable composition, comprising peptide YY analogs;and administering the pharmaceutically acceptable composition to themammal, said peptide YY analogs being delivered in an amount and underconditions such that activation of a cholinergic intestino-fugalpathway, one or more prevertebral ganglionic pathways, a gangalion tocentral nervous system pathway, the adrenergic efferent neural pathway,the serotonergic interneuron and/or the opioid interneuron issubstantially reduced by the action of said peptide YY analogs, wherebythe sensation of esophageal, gastric, biliary, intestinal, colonic orrectal pain experienced by the human subject is reduced.
 10. The methodof claim 9, wherein administering the pharmaceutically acceptablecomposition to the mammal further comprises administering thepharmaceutically acceptable composition by a delivery route selectedfrom the group consisting of oral, intravenous, intraperitoneal, andnasal.
 11. A method of manipulating post-prandial visceral blood flow tothe gastrointestinal tract of a mammal having a cholinergic afferentneural pathway projecting from a peptide YY-sensitive primary sensoryneuron in the intestinal wall to a prevertebral celiac ganglion andhaving an adrenergic efferent neural pathway projecting from saidganglion to one or more enterochromaffin cells in the intestinal mucosaand/or to a serotonergic interneuron linked in a myenteric plexus to anopioid interneuron, said opioid interneuron also being linked by anintestino-fugal opioid pathway projecting to said ganglion, withadditional neural connections to the central nervous system and back tothe gut projecting from the ganglion, comprising: providing apharmaceutically acceptable composition, comprising an active agentselected from the group consisting of (A) peptide YY analogs, and (B)antagonists of receptors for (A); and administering the pharmaceuticallyacceptable composition to the mammal, said active agent being deliveredin an amount and under conditions such that the cholinergicintestino-fugal pathway, prevertebral ganglionic pathways, gangalion tocentral nervous system pathways, central nervous system pathways,adrenergic efferent neural pathway, the serotonergic interneuron and/orthe opioid interneuron are activated by the action of (A), whereby theflow of blood to the gastrointestinal tract is increased, or such thatactivation of the cholinergic intestino-fugal pathway, prevertebralganglionic pathways, gangalion to central nervous system pathways, theadrenergic efferent neural pathway, the serotonergic interneuron and/orthe opioid interneuron is blocked by the action of (B), whereby the flowof blood to the gastrointestinal tract is decreased.
 12. The method ofclaim 11, wherein administering the pharmaceutically acceptablecomposition to the mammal further comprises administering thepharmaceutically acceptable composition by a delivery route selectedfrom the group consisting of oral, intravenous, intraperitoneal, andnasal.